@article {pmid41844465,
year = {2026},
author = {Liu, J and Cao, F and Li, Z and Zeng, H and Zhou, M and He, Q and Jiang, W and Li, Y and Yan, J},
title = {Association between exogenous hormone use and dementia: A prospective cohort study and synthetic analysis.},
journal = {Maturitas},
volume = {208},
number = {},
pages = {108895},
doi = {10.1016/j.maturitas.2026.108895},
pmid = {41844465},
issn = {1873-4111},
abstract = {OBJECTIVES: To investigate the controversial association between exogenous hormone use (EHU) and dementia, with a focus on subtype-specific risks.

STUDY DESIGN: This prospective cohort study followed 273,069 women in the UK Biobank over 3,802,608 person-years, identifying 4,710 dementia cases.

MAIN OUTCOME MEASURES: Cox models assessed use of oral contraceptive (OC) and hormone replacement therapy (HRT) in relation to all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and frontotemporal dementia (FTD) across treatment durations. Subgroup analyses were stratified by age, ethnicity, APOE status, education, income, and reproductive factors. A systematic review was conducted to synthesize existing evidence.

RESULTS: In the cohort study, OC use was associated with reduced risks of all-cause dementia (HR 0.90, 95%CI 0.84-0.95), AD (HR 0.87, 95%CI 0.79-0.95), and VaD (HR 0.81, 95%CI 0.70-0.93), particularly after 4-14 years of use. HRT showed no significant association with increased dementia risk. Synthesized results largely corroborated these findings: OC use was associated with reduced risks of dementia (HR 0.90, 95%CI 0.89-0.92); and although four European studies reported a moderately increased AD risk after post-menopausal HRT use, neither cohort-based studies (HR 0.98, 95%CI 0.90-1.06) nor traditional case-control studies (OR 1.00, 95%CI 0.90-1.11) found an association between HRT and dementia.

CONCLUSIONS: Our combined evidence does not support an increased risk of dementia associated with OC use; similarly, no clear association was observed between HRT and increased dementia risk. Clinical decisions on EHU should be individualized, balancing overall benefits against potential risks.},
}

@article {pmid41844585,
year = {2026},
author = {Yang, M and Tong, L and Guo, Z and Tan, Z and Holmes, TC and Yu, Z and Xu, X},
title = {Evaluating the potential of acupuncture for Alzheimer's disease treatment: A meta-analysis and systematic review of mouse model studies.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03923-9},
pmid = {41844585},
issn = {2158-3188},
abstract = {Acupuncture is an ancient practice that was developed within the framework of traditional Chinese medicine. While acupuncture has been recently proposed as a therapy for Alzheimer's disease (AD), acupuncture effects are not well understood in terms of neural mechanisms. Here, we review and examine the studies that used AD mouse models and analyze the experiments where researchers administered electroacupuncture (EA) to AD mice to assess the potential therapeutic impact of acupuncture on disease pathology and cognitive function in controlled laboratory settings. We analyzed 29 relevant PubMed articles published between January 2014 and July 2025. Our results reveal that EA significantly reduces both amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels and neuroinflammatory biomarkers, including molecular signatures for activated microglia and astrocytes in the brain. EA also enhances cognitive functions. While no study directly compared acupoint strategies, the indirect comparisons in our network analysis suggest that GV20 has potential as a therapeutic target for AD. Our present meta-analysis and review of literature add to the evidence of integrative health practices for acupuncture-based Alzheimer's disease treatment.},
}

@article {pmid41845487,
year = {2026},
author = {Wu, J and Ge, Y and Zhang, L and Huang, J and Huang, N and Luo, Y},
title = {Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway.},
journal = {Stem cell research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13287-026-04954-1},
pmid = {41845487},
issn = {1757-6512},
support = {ZK [2024]-680//Science and Technology Department of Guizhou Province/ ; ZK [2021]-570//Science and Technology Department of Guizhou Province/ ; 82160858//National Natural Science Foundation of China/ ; HZ-2022-45, [2024] No. 6, HZ-2025-06//Zunyi Science and Technology Bureau/ ; ZSYS(2025)040//Guizhou Provincial Science and Technology Department/ ; },
abstract = {Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer's disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.},
}

@article {pmid41845577,
year = {2026},
author = {Zhao, J and Huang, R and Bu, N and Wang, H and Zhang, S and Pan, Y and Su, Y and Wei, Z and Chen, Y and Li, Y and Dong, X and Li, Y and Wei, J and Zhao, X and Lin, L and Sun, K},
title = {Advances in the Use of Traditional Chinese Medicine Prescriptions for Alzheimer's Disease.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {26},
number = {3},
pages = {e70157},
doi = {10.1111/psyg.70157},
pmid = {41845577},
issn = {1479-8301},
support = {NGBJ-2020-30//The Doctoral Scientific Research Foundation for Returned Scholars from Nanyang Institute of Technology/ ; YJS2025GZZ58//Postgraduate Education Reform and Quality Improvement Project of Henan Province/ ; 242102111123//Henan Provincial Science and Technology Research Project/ ; 222102310357//Science and Technology Research Project of Henan Provincial/ ; },
mesh = {*Alzheimer Disease/drug therapy/therapy ; Humans ; *Medicine, Chinese Traditional/methods ; *Drugs, Chinese Herbal/therapeutic use ; Gastrointestinal Microbiome ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterised by progressive cognitive and memory impairment. Recent research on neurodegenerative diseases has demonstrated the importance of the brain-gut axis, which has gradually become a hotspot in the field of AD research. The gut microbiota has been shown to be involved in the pathogenesis and treatment of neurodegenerative diseases such as AD. Traditional Chinese medicine (TCM) has been used for millennia in China for the treatment of disease. This article summarises recent research on the use of TCM prescriptions for treating AD. It is hoped that this review will provide new ideas for the treatment of AD.},
}

*Alzheimer Disease/drug therapy/therapy
Humans
*Medicine, Chinese Traditional/methods
*Drugs, Chinese Herbal/therapeutic use
Gastrointestinal Microbiome

@article {pmid41845988,
year = {2026},
author = {Zhu, X and Lai, X and Deng, J and Long, Y},
title = {Naturally occurring antibodies against ASC reduced in Alzheimer's disease and alleviating AD-type pathology in APP/PS1 mouse.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115728},
doi = {10.1016/j.expneurol.2026.115728},
pmid = {41845988},
issn = {1090-2430},
abstract = {The disruption or increased permeability of the blood-brain barrier (BBB) results in dysregulated autoantibody profiles in Alzheimer's disease (AD) patients. Naturally occurring antibodies against ASC (NAbs-ASC), which are present in human blood, can block the ability of ASC specks to seed Aβ aggregation. However, the characteristics and functions of NAbs-ASC in AD remain unclear. In this study, we found that plasma levels of NAbs-ASC were reduced in AD patients and showed a negative correlation with the severity of cognitive impairment and with plasma Aβ42/40 ratios. NAbs-ASC treatment reduced Aβ production and attenuated Aβ-induced cytotoxicity in AD cell models. Furthermore, passive immunization with NAbs-ASC or active immunization with ASC peptides improved cognitive function, attenuated Aβ deposition, reduced Tau phosphorylation, inhibited neuroinflammation and apoptosis, and improved synaptic plasticity in APP/PS1 mice. These findings support that NAbs-ASC may be an important physiological protective factor for AD, and that Immunotherapy targeting ASC may be a potential therapeutic intervention for the disease.},
}

@article {pmid41845989,
year = {2026},
author = {Zhao, Y and Chen, W and Zhou, F},
title = {IL-1β neutralization ameliorates cognitive deficits and tau pathology in a mouse model of Alzheimer's disease with Hyperhomocysteinemia.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115729},
doi = {10.1016/j.expneurol.2026.115729},
pmid = {41845989},
issn = {1090-2430},
abstract = {BACKGROUND: Hyperhomocysteinemia (HHcy) is an important risk factor for Alzheimer's disease (AD), but its differential effects on tau pathology and beta-amyloid (Aβ) deposition, as well as the key mediating molecules involved, remain unclear. This study investigates how HHcy influences AD pathology and examines whether interleukin-1β (IL-1β) neutralization can mitigate HHcy-accelerated neurodegeneration.

METHODS: Female 12-month-old 3 × Tg-AD mice were supplemented with methionine water for 7 weeks to induce HHcy. Brain tissues were analyzed for Aβ deposition, tau phosphorylation, oligomerization, and neurofibrillary tangle formation using ELISA, immunohistochemistry, Western blot, and Thioflavin S staining. To assess the role of IL-1β, HHcy-AD mice were treated with an anti-IL-1β monoclonal antibody (mAb; 100 μg, twice weekly for two weeks). Moreover, behavioral performance was evaluated using the Morris water maze for the effect of IL-1β neutralization.

RESULTS: HHcy significantly exacerbated tau pathology, increasing oligomeric tau levels, hyperphosphorylation (AT-8, Ser396, Thr231), and neurofibrillary tangles, particularly in the cortex. In contrast, HHcy had minimal effects on Aβ deposition, only increasing insoluble Aβ1-40. Anti-IL-1β mAb treatment reduced tau phosphorylation and oligomerization, coinciding with inactivation of hippocampal GSK3β (increased p-Ser9). The mAb also improved cognitive function but showed selective effects on Aβ pathology and differentially modulated glial responses across brain regions.

CONCLUSION: HHcy preferentially exacerbates tauopathy rather than amyloidosis in 3 × Tg-AD mice. IL-1β neutralization ameliorates tau-related pathology and cognitive deficits, likely through regional suppression of GSK3β activity, highlighting its potential as a therapeutic strategy for tau-focused AD interventions.},
}

@article {pmid41847148,
year = {2026},
author = {Yuan, X and Tang, Q and Wang, T},
title = {Nanotechnology-based targeted delivery strategies for the treatment of Alzheimer's disease.},
journal = {Nanoscale advances},
volume = {},
number = {},
pages = {},
pmid = {41847148},
issn = {2516-0230},
abstract = {Alzheimer's disease (AD), as a common neurodegenerative disorder, seriously affects human health. However, the treatment of AD has always faced significant challenges and has attracted extensive attention in medical research. In recent years, nanoparticle-based therapeutic strategies have been identified as a promising direction in AD research due to their unique advantages and potential. These strategies leverage the distinctive physical and chemical properties of nanomaterials, enabling them to effectively traverse the blood-brain barrier and directly target pathological sites, thereby minimizing damage to normal tissues and enhancing therapeutic efficacy. This approach holds considerable promise for AD treatment. Current literature indicates that nanomedicines can deliver therapeutic agents, such as approved pharmaceuticals, natural compounds, antibodies, and metal nanoparticles, directly to lesion sites, thereby reducing collateral damage to healthy tissues and improving treatment outcomes. With continuous advancements in nanotechnology and ongoing scientific investigations, there is potential for developing safer and more effective treatment options for AD patients in the future. This review aims to summarize recent developments in nanoparticle-based strategies for AD therapy and elucidate their mechanisms of action, providing new insights for the future development and advancement of nanomedicines in this domain.},
}

@article {pmid41847265,
year = {2025},
author = {Agtas, G and Singh, K and Park, H and Mukerji, S},
title = {Plasma Biomarkers and Cognitive Decline in HIV: Findings from Two U.S. Cohorts.},
journal = {TouchREVIEWS in infectious diseases},
volume = {4},
number = {1},
pages = {22-27},
pmid = {41847265},
issn = {2755-113X},
abstract = {With advances in antiretroviral treatment, the population of older people living with HIV (PLWH) is increasing rapidly, leading to a rise in cognitive impairment related to both HIV and aging. Plasma biomarkers have been extensively investigated as non-invasive tools to help detect neurodegeneration in PLWH. This review compares cross-sectional and longitudinal findings from two recent substudies conducted within U.S. cohorts, the AIDS Clinical Trials Group HAILO study and the Women's Interagency HIV Study (WIHS), both of which investigated the relationship between plasma biomarkers and cognitive performance in PLWH. This review focuses on the common biomarkers evaluated in both studies: neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Both studies demonstrated longitudinal associations between elevated NfL levels and poor cognitive performance, particularly in processing speed. In contrast, GFAP showed inconsistent associations, suggesting its utility will be limited in clinical settings. Given that effect sizes across both studies ranged from small to modest, further validation in diverse aging cohorts with domain specific cognitive assessments is needed before routine clinical use.},
}

@article {pmid41847685,
year = {2026},
author = {Si, C and Ma, L and Ding, W and Tian, Y and Zhang, J and Cao, H and Shao, Y and Fan, Z},
title = {Human umbilical cord mesenchymal stem cells therapy for Alzheimer's disease: a systematic review and meta-analysis of mouse models.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1783757},
pmid = {41847685},
issn = {1664-2295},
abstract = {OBJECTIVE: Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application.

METHODS: In accordance with the PRISMA guidelines, we systematically searched four major databases to identify randomized controlled trials involving hUCMSCs in AD mouse models. We used the standardized mean difference (SMD) to synthesize effect sizes and performed subgroup analyses based on pre-defined transplantation routes and doses.

RESULTS: A total of 13 studies were included in the analysis. The meta-analysis revealed that hUCMSCs transplantation significantly improved spatial learning and memory in AD model mice, with a marked reduction in escape latency (SMD = -2.55; 95% CI: -3.34 to -1.75; I [2] = 77.9%, random-effects model). Additionally, it significantly lowered brain β-amyloid levels (SMD = -5.34; 95% CI: -7.21 to -3.47; I [2] = 80.3%), increased brain-derived neurotrophic factor (SMD = 4.25; 95% CI: 3.18 to 5.31), and reduced neuronal apoptosis (SMD = -4.96; 95% CI: -6.52 to -3.41). Subgroup analyses further revealed that efficacy was significantly dose- and route-dependent. For cognitive improvement, intravenous injection of medium to high doses (≥1 × 10[6] cells) was most effective and robust. For amyloid-β clearance, low-dose administration via intravenous, lateral ventricle, and cortical routes showed significant efficacy, whereas bilateral hippocampal injection did not yield significant benefits.

CONCLUSION: Human umbilical cord mesenchymal stem cells can improve behavioral and pathological outcomes in AD mouse models via multiple mechanisms of action. The intravenous route using medium to high doses emerges as a critical factor for achieving optimal effects, providing important evidence and informing future experimental design and clinical translational research.},
}

@article {pmid41848189,
year = {2026},
author = {Shrewsbury, SB},
title = {DHE - past, present, and future: a narrative review.},
journal = {Pain management},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17581869.2026.2644524},
pmid = {41848189},
issn = {1758-1877},
abstract = {Dihydroergotamine (DHE) was first approved in 1946 for the acute treatment of migraine. Its efficacy when administered as an intravenous (IV) injection explains its enduring use in the management of migraine today. More recently, attention has been focused on the development of formulations delivered by the inhalational route to either the nasal mucosa or lung with the objective of providing a product that enables easy, needle-free, "at-home" use that is rapidly effective. Three new DHE products for migraine (two administered by nasal delivery) have been Food and Drug Administration (FDA) approved in the past five years with two others using pulmonary delivery in clinical development attempting to optimize outcomes for subjects requiring "at-home" migraine treatment. This narrative review describes those DHE development programs, and others that have failed, with the objective of providing a broad perspective on various approaches, including those that may be more likely to achieve the goals of high efficacy rates, rapid relief, and convenience of use. In addition, DHE has been investigated for potential repurposing of other indications. These too are described.},
}

@article {pmid41849958,
year = {2026},
author = {Iwata, A and Sakata, Y and Koizumi, K and Endo, A and Kuang, W and Sumitomo, K and Ishii, M},
title = {Interim analysis of all-case post-marketing surveillance study in Japan: lecanemab in patients with early Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100541},
doi = {10.1016/j.tjpad.2026.100541},
pmid = {41849958},
issn = {2426-0266},
abstract = {BACKGROUND: Lecanemab is a monoclonal antibody targeting amyloid-beta protofibrils, indicated for patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease.

OBJECTIVES: This study reports interim findings of an ongoing, multicenter, prospective, observational post-marketing study for all patients treated with lecanemab in routine clinical practice in Japan, focusing on amyloid-related imaging abnormalities (ARIAs) and infusion-related reactions primarily observed during up to 28 weeks after treatment initiation.

METHODS: Patients treated with lecanemab at any medical institutions across Japan are included in the study. Data are collected using an electronic data capture system via standardized case report forms (CRFs). Study items included the incidence of ARIA, ARIA-edema or effusion (-E), ARIA-hemorrhage (-H: cerebral microhemorrhages, superficial siderosis, and macrohemorrhage), and infusion-related reactions, reported as adverse drug reactions.

RESULTS: As of July 5, 2025, CRFs from 2675 patients were collected, of whom 2672 had data available for the interim analysis. The median age was 76.0 years, and 62.6 % (1672/2672) of patients were diagnosed with MCI. At Week 28, 7.3 % (195/2672) of patients discontinued treatment, with a mean treatment duration of 189.6 ± 34.4 days. Among 2634 patients confirmed to have undergone MRI scans after treatment initiation, ARIA was observed in 7.1 % (188/2634) of patients, ARIA-E in 3.0 % (78/2634), and ARIA-H in 5.2 % (137/2634). Serious ARIA-H (macrohemorrhage) occurred in two patients (0.1 %). Infusion-related reactions were observed in 17.0 % (455/2672), including 0.7 % (18/2672) serious cases. The proportion of patients who experienced ARIA was highest in patients with apolipoprotein E (APOE) ε4 homozygotes.

CONCLUSION: This interim analysis represents one of the largest real-world lecanemab cohorts reported globally to date. Although absolute rates are not directly comparable with those from clinical trials, the trends in ARIA distributions across APOE genotypes and infusion-related reactions were comparable to those observed in clinical trials.},
}

@article {pmid41839135,
year = {2025},
author = {Cortés-Rodríguez, A and Alves-Gomes, L and Losa-Iglesias, ME and Gómez-Salgado, J and Becerro-de-Bengoa-Vallejo, R and Saavedra-García, MA and López-López, D and Jiménez-Cebrián, AM},
title = {Repercussion of kinesiophobia in ankylosing spondylitis: a case-control study.},
journal = {Gaceta medica de Mexico},
volume = {161},
number = {4},
pages = {379-384},
doi = {10.24875/GMM.25000033},
pmid = {41839135},
issn = {0016-3813},
mesh = {Humans ; Male ; Case-Control Studies ; *Spondylitis, Ankylosing/psychology/complications ; Female ; Middle Aged ; *Phobic Disorders/epidemiology/etiology ; Adult ; *Alzheimer Disease/psychology/complications ; Surveys and Questionnaires ; *Fear/psychology ; Aged ; Movement ; Kinesiophobia ; },
abstract = {BACKGROUND: Kinesiophobia, or fear of movement, is closely related to ankylosing spondylitis. This fear can make it profoundly difficult to relieve symptoms by discouraging participation in therapeutic exercises.

OBJECTIVES: The aim of this study was to assess and contrast the perceived levels of safety and confidence during movement tasks.

MATERIALS AND METHODS: A total of 104 individuals were recruited. This group was divided into cases and controls, ensuring alignment in terms of age, sex, and body mass index. Demographic information was collected and scores on the Tampa Scale for Kinesiophobia -11 questionnaire were recorded for further comparison.

RESULTS: All individuals with Alzheimer's disease (AD) suffered from some degree of kinesiophobia, and 77% had moderate to maximum scores. In contrast, in the control group, without AEs, none presented maximum levels, and 76.9% presented scores with mild or no levels of kinesiophobia. The comparison between groups showed a statistically significant difference.

CONCLUSION: Kinesiophobia was significantly higher in AD patients compared to healthy individuals, emphasizing the need for specific interventions to manage this condition in treatment plans.},
}

Humans
Male
Case-Control Studies
*Spondylitis, Ankylosing/psychology/complications
Female
Middle Aged
*Phobic Disorders/epidemiology/etiology
Adult
*Alzheimer Disease/psychology/complications
Surveys and Questionnaires
*Fear/psychology
Aged
Movement
Kinesiophobia

@article {pmid41839797,
year = {2026},
author = {Fallone, M and Sivananthan, M and Joseph, M},
title = {Donepezil for Korsakoff Syndrome.},
journal = {American journal of therapeutics},
volume = {},
number = {},
pages = {},
doi = {10.1097/MJT.0000000000002102},
pmid = {41839797},
issn = {1536-3686},
abstract = {BACKGROUND: Korsakoff syndrome is a neurocognitive disorder characterized by memory impairment and confabulation caused by severe or prolonged thiamine deficiency. It is preceded by a type of delirium called Wernickes Encephalopathy, which is reversible. However, once a patient progresses to Korsakoff syndrome, treatment options are limited because there are currently no FDA-approved medications for Korsakoff syndrome. Donepezil is an acetylcholinesterase inhibitor that has shown efficacy in Alzheimer disease and has been theorized to have benefit in other neurologic disorders as well. In this case, we present a patient with Korsakoff syndrome who had improvement in symptoms after starting donepezil.

DATA SOURCE: The information presented here is derived directly from the clinical records and observations of the patient under our care.

FINDINGS AND LIMITATIONS: The case presented here demonstrates improvement in cognition, motivation, and affect in Korsakoff dementia with the use of donepezil. Limitations of this case study and those alike include lack of generalizability, retrospective design, and absence of a control.

CONCLUSIONS: The off-label use of donepezil for Korsakoff syndrome in this case and others has been shown to be beneficial and well tolerated. Ultimately, larger studies are needed to determine safety and efficacy.},
}

@article {pmid41839802,
year = {2026},
author = {Xu, YR and Tao, Y and Lish, AM and Li, S and Ostaszewski, BL and Anderson, AK and Young-Pearse, T and Lawton, TL and Yang, HS and Walsh, DM and Yang, T and Selkoe, DJ},
title = {Novel Monoclonal Antibody Detects Small Aβ Oligomers More Sensitively Than Lecanemab in Alzheimer's Disease CSF, Serum and Culture Media.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78196},
pmid = {41839802},
issn = {1531-8249},
abstract = {OBJECTIVE: Aqueously diffusible oligomers of the amyloid β-protein (oAβ) are neurotoxic and play a role in neuronal dysfunction in Alzheimer's disease (AD). Accurate quantification of oAβ in brains and biofluids could be valuable for understanding and monitoring AD. In this study, we aimed to examine the ability of 2 antibodies to quantify diffusible oAβ in AD tissue and biofluids.

METHODS: Two oligomer preferring antibodies, 71A1 and lecanemab, were compared to quantify oAβ assemblies in AD brain tissue, cerebrospinal fluid (CSF), serum, and culture media of human neurons expressing Aβ-altering mutations.

RESULTS: Both antibodies recognized synthetic aggregates of Aβ and detected significantly elevated oAβ levels in aqueous extracts of AD versus control brain tissues. Only 71A1 sensitively quantified diffusible oAβ species in CSF, neuronal media, and serum.

INTERPRETATION: Whereas lecanemab is an effective plaque-clearing immunotherapy that robustly detects higher-order Aβ aggregates in AD brain, its preferred Aβ targets are present at very low levels in biofluids. Our results demonstrate that 71A1 detects low-n, diffusible Aβ oligomers that predominate in CSF, serum, and neuronal media that associate with AD-related pathology. Together, these findings indicate that Aβ oligomer populations distribute differently in brain tissue versus biofluids and inform the selection of assays for monitoring oligomers during AD progression and treatment. ANN NEUROL 2026.},
}

@article {pmid41840318,
year = {2026},
author = {Paliwal, S and Bhardwaj, JS and Yang, CH and Taliyan, R},
title = {Unravelling Epigenetic Modulation via MicroRNA Delivery: A Therapeutic Frontier for Alzheimer's.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41840318},
issn = {1559-1182},
support = {BT/INF/22/SP42545/2021//Department of Biotechnology- BUILDER/ ; },
mesh = {*MicroRNAs/administration & dosage/genetics/metabolism ; *Alzheimer Disease/genetics/therapy ; Humans ; *Epigenesis, Genetic ; Animals ; *Gene Transfer Techniques ; tau Proteins/metabolism ; },
abstract = {Alzheimer's disease (AD) is a common form of dementia that primarily affects the elderly population. Several signalling pathways, including Wnt/β-catenin and PI3K/Akt, are significantly affected, disrupting normal physiological processes such as neurogenesis, neuronal survival, neuroinflammation, and BBB disruption, all of which contribute to the progression of AD-like conditions. The current study seeks to investigate and evaluate the involvement of the PI3K-Akt and Wnt/β-catenin pathways in AD, as well as epigenetic regulators that may alter these pathways and be employed as a treatment to improve AD-like conditions. A class of epigenetic regulators known as miRNAs, or short non-coding RNAs, greatly affects gene expression by preventing translation or encouraging target gene destruction. This review will focus on how miRNAs affect Aβ peptide accumulation, hyperphosphorylated tau protein aggregation, and neuroinflammation. In addition, miRNA delivery through exosomes, a lipid nanoparticle, has also been explored in later sections. Our knowledge will assist in creating new miRNA-based therapeutics involving mimics/inhibitors and advance our understanding of how miRNAs control gene expression.},
}

*MicroRNAs/administration & dosage/genetics/metabolism
*Alzheimer Disease/genetics/therapy
Humans
*Epigenesis, Genetic
Animals
*Gene Transfer Techniques
tau Proteins/metabolism

@article {pmid41843546,
year = {2026},
author = {Stingl, J and Guyette, FX and Drábek, T},
title = {Accidental Environmental Hypothermia in a Nonagenarian Resulting in Cardiac Arrest.},
journal = {Prague medical report},
volume = {127},
number = {1},
pages = {39-43},
doi = {10.14712/23362936.2026.6},
pmid = {41843546},
issn = {1214-6994},
mesh = {Humans ; Female ; *Heart Arrest/etiology/therapy ; *Hypothermia/complications/therapy ; Aged, 80 and over ; },
abstract = {Accidental hypothermia after environmental exposure and/or impaired thermoregulation resulting in significant decrease in body temperature and cardiac arrest (CA) is linked to 1,500 deaths annually in the United States. Hypothermic CA treatment has specific presentation and clinical features. With appropriate treatment, its survival can reach 27-70%, contrasting ~ 10% in medical CA. Majority of accidental hypothermic CA survivors recover with favourable neurologic outcome. An integrated, dedicated multi-disciplinary team-approach is essential to maximize the chances of survival. We report on a 91-year-old female who was found outside and unresponsive in freezing temperatures. During transport, she required bag-and-mask ventilation. An esophageal temperature recorded 24.5 °C. Shortly after rapid sequence intubation, she developed CA. She was successfully resuscitated with chest compressions, epinephrine, atropine, and two defibrillations. Due to persistent hypothermia and bradycardia, she was rewarmed using extracorporeal membrane oxygenation. Perioperative transesophageal echocardiography showed normal cardiac function. She was extubated the next day. She remained stable for the rest of her hospital stay without focal neurological deficits on serial examinations. However, her post-arrest stay was complicated by acute delirium, likely from underlying dementia, with a waxing and waning level of consciousness, confusion, agitation and hallucinations. She was discharged on post-operative day 5. Her long-term recovery was complicated by repeated aspiration pneumonias, and gradual decline of her mental status due to Alzheimer's dementia. She died approximately two years later at the age of 93. Thus, full neurologic recovery remains possible after CA induced by severe hypothermia from environmental exposure, despite extreme age and frailty.},
}

Humans
Female
*Heart Arrest/etiology/therapy
*Hypothermia/complications/therapy
Aged, 80 and over

@article {pmid41844366,
year = {2026},
author = {Duan, J and Engelman, CD and Lu, Q and Kang, H},
title = {Comparison of Methods for Sensitivity Analysis of Heterogeneous Treatment Effects in Observational Studies and Application to Alzheimer's Disease and Cognitive Decline.},
journal = {Statistics in medicine},
volume = {45},
number = {6-7},
pages = {e70446},
doi = {10.1002/sim.70446},
pmid = {41844366},
issn = {1097-0258},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Cognitive Dysfunction/therapy/etiology ; *Observational Studies as Topic/statistics & numerical data/methods ; Male ; Models, Statistical ; Female ; Treatment Outcome ; Sleep Wake Disorders/complications ; Treatment Effect Heterogeneity ; },
abstract = {In Alzheimer's disease (AD) research, many observational studies have shown that the effect of sleeping quality, a modifiable risk factor, on cognitive decline is heterogeneous, where some adults experience faster rates of cognitive decline compared to others. However, these effects are likely confounded by unmeasured confounders, and the sensitivity of these effects to unmeasured confounders may be heterogeneous, where one subgroup's treatment effect is more sensitive than that of another subgroup. Unfortunately, compared to the overall treatment effect, there are limited investigations about the sensitivity of heterogeneous treatment effects to unmeasured confounding. The paper presents and compares methods for sensitivity analysis of heterogeneous effects in observational studies based on Rosenbaum's model for sensitivity analysis. We show that, unlike the sensitivity analysis of the overall treatment effect, the sensitivity of heterogeneous treatment effects depends on the variation in the effect sizes across subgroups and the correction for multiple testing. The data analysis further supports our findings where the overall effect of sleep disturbances on cognitive decline is significant (p $$ p $$ -value = 5 . 55 × 1 0 - 5 $$ 5.55\times 1{0}^
{-5}
$$). Also, the effect is more severe among males (p $$ p $$ -value = 2 . 00 × 1 0 - 4 $$ 2.00\times 1{0}^
{-4}
$$) and insensitive to a moderate degree of unmeasured confounding. Finally, we offer an easy-to-use R software to carry out the sensitivity analyses for heterogeneous treatment effects.},
}

Humans
*Alzheimer Disease/therapy
*Cognitive Dysfunction/therapy/etiology
*Observational Studies as Topic/statistics & numerical data/methods
Male
Models, Statistical
Female
Treatment Outcome
Sleep Wake Disorders/complications
Treatment Effect Heterogeneity

@article {pmid41844398,
year = {2026},
author = {Hou, Y and Huang, G and Liu, Y and Qiu, Y and Ye, P and Bi, L and Zheng, P and Xu, Y and Wu, S and Wei, C and Jin, H},
title = {Rescue of Cognitive Deficits in a Mouse Model of Alzheimer's Disease with a Novel Brominated P2 × 7 Receptor Antagonist.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00127},
pmid = {41844398},
issn = {1948-7193},
abstract = {P2 × 7 receptor (P2 × 7R) represents a promising therapeutic target for Alzheimer's disease (AD), given its marked upregulation in neuroinflammation and involvement in amyloid-β (Aβ) and tau pathology. Although several P2 × 7R antagonists with high central nervous system (CNS) penetration and cross-species activity have been developed, none have yet reached clinical use, underscoring the need for optimized agents suitable for chronic neurological conditions. In this study, we designed a series of brominated P2 × 7R antagonists based on a prominent antagonist Lu AF27139, among which the lead compound YH1 exhibited favorable lipophilicity, brain penetration, plasma stability, and receptor binding. In transgenic AD mice, YH1 treatment significantly alleviated cognitive deficits, reduced cerebral P2 × 7R expression, and decreased Aβ load. Using [18]F-GSK1482160 positron emission tomography (PET) imaging, we observed a significant decline of P2 × 7R binding, indicating that YH1-mediated cognitive improvement involves targeted suppression of P2 × 7R-driven neuroinflammation. These results establish a precision AD-oriented optimization of the Lu AF27139 scaffold, demonstrate measurable PK improvements, and provide the first PET-verified P2 × 7R target engagement in an AD model, supporting translational relevance.},
}

@article {pmid41830246,
year = {2026},
author = {Li, H and Zhou, HL and Chen, L and Wu, B},
title = {[Occurrence Characteristics and Associated Factors of Alzheimer's Disease Drugs in Wastewater in China].},
journal = {Huan jing ke xue= Huanjing kexue},
volume = {47},
number = {3},
pages = {1657-1664},
doi = {10.13227/j.hjkx.202503326},
pmid = {41830246},
issn = {0250-3301},
mesh = {China ; *Wastewater/chemistry/analysis ; *Alzheimer Disease/drug therapy ; *Water Pollutants, Chemical/analysis ; Humans ; Memantine/analysis/therapeutic use ; Environmental Monitoring ; Rivastigmine/analysis ; Galantamine/analysis/therapeutic use ; Donepezil ; Indans/analysis ; Piperidines/analysis ; Waste Disposal, Fluid ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disease. The usage of its therapeutic drugs is increasing with the intensification of population aging. These drugs cannot be completely metabolized in the human body and enter wastewater systems in the form of the originals or metabolites. In-depth investigation of the occurrence characteristics of these drugs in wastewater is of great significance for effective control and management. The concentrations and associated factors of four main AD drugs (donepezil, rivastigmine, galantamine, and memantine) and their metabolites in the influent of 210 wastewater treatment plants across 31 Chinese provinces were analyzed. The results indicated that detection rates of the above drugs in wastewater were high, with concentrations ranging from 7.47-21.60 ng·L[-1]. Among them, the concentration of donepezil was significantly higher in East China and the Northwest and Northeast regions than that in Central China; the concentrations of rivastigmine and galantamine in Southwest China were significantly higher than those in East China; and the concentrations of memantine in Northwest and North China were significantly higher than those in East China. The above results indicated that the occurrence of these drugs showed a significant regional difference. Further, the AD drugs and metabolites with detection rates above 90% and excretion rates exceeding 20% (donepezil, rivastigmine metabolite, galantamine metabolite, and memantine) were chosen as biomarkers to evaluate AD prevalence. The prevalence of AD in different regions was estimated by wastewater-based epidemiology method, and the results were highly consistent with official statistical data. These results showed that the concentrations of AD drugs in wastewater influent were closely related to the AD prevalence. Additionally, correlation analysis also found that socioeconomic factors (such as stress, aging population, level of economic development, and health care services) had a significant positive correlation with the AD prevalence, indicating that socioeconomic factors may influence the occurrence of AD drugs in wastewater by affecting the AD prevalence. These results provide a scientific basis for further understanding of the characteristics of AD drugs in wastewater treatment plants and the development of corresponding control measures.},
}

China
*Wastewater/chemistry/analysis
*Alzheimer Disease/drug therapy
*Water Pollutants, Chemical/analysis
Humans
Memantine/analysis/therapeutic use
Environmental Monitoring
Rivastigmine/analysis
Galantamine/analysis/therapeutic use
Donepezil
Indans/analysis
Piperidines/analysis
Waste Disposal, Fluid

@article {pmid41830758,
year = {2026},
author = {Thibault, EG and Del Carmen Montenegro, G and Becker, JA and Price, JC and Healy, BC and Hanseeuw, BJ and Buckley, RF and Jacobs, HIL and Properzi, MJ and Sperling, RA and Johnson, KA and Farrell, ME},
title = {Amyloid spatial extent with florbetapir-PET for early detection of preclinical Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100529},
doi = {10.1016/j.tjpad.2026.100529},
pmid = {41830758},
issn = {2426-0266},
abstract = {BACKGROUND: Prevention of Alzheimer's disease (AD) requires biomarkers sensitive to the earliest amyloid-β (Aβ) deposits.

OBJECTIVES: To characterize performance of a recently-developed Aβ-PET spatial extent metric (EXT) for early Aβ detection using [18][F]-florbetapir (FBP)-PET, evaluating its sensitivity, reliability, and associations with plasma pTau217, tau-PET, and cognition.

DESIGN: Longitudinal study with up to 5.5 years of PET, plasma and cognitive measures.

SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) Study and its companion screen-fail study Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) conducted across 67 international sites.

PARTICIPANTS: 1118 cognitively unimpaired older adults from the A4 placebo arm and LEARN.

MEASUREMENTS: EXT (% of neocortex above region-specific thresholds), global Aβ SUVR, plasma pTau217, medial temporal (MTL) and temporal neocortical (nTEMP) tau-PET SUVR, and Preclinical Alzheimer Cognitive Composite (PACC).

RESULTS: EXT showed high cross-sectional reliability and longitudinal stability. Using EXT reclassified 21.4% of SUVR-participants from Aβ- to Aβ+ and predicted who would progress to SUVR+ 5.5 years later with 83% sensitivity and 94% specificity. In SUVR- individuals, higher pTau217 associated with greater SUVR only within EXT+ individuals. Baseline EXT outperformed SUVR in predicting MTL tau proliferation. For neocortical tau SUVR and PACC change, EXT was the better predictor in earlier Aβ stages (while Aβ spread) while SUVR was superior later (after Aβ was widespread).

CONCLUSIONS: EXT is a robust, generalizable PET metric that detects Aβ before global positivity and early Aβ-related changes in tau and cognition, supporting its relevance for trial enrichment and early therapeutic monitoring in AD prevention trials.},
}

@article {pmid41830836,
year = {2026},
author = {Xu, G and Gao, P and Li, H and Fang, Y and Yang, Z},
title = {Research progress of PTP1B inhibitors and degraders.},
journal = {European journal of medicinal chemistry},
volume = {309},
number = {},
pages = {118770},
doi = {10.1016/j.ejmech.2026.118770},
pmid = {41830836},
issn = {1768-3254},
abstract = {Protein tyrosine phosphatase 1B (PTP1B), a member of the PTP superfamily, inhibits insulin signaling by dephosphorylating the insulin receptor (IR) and its substrates (IRS), making it an important therapeutic target for diabetes and obesity, with potential applications in treating metabolic syndrome. Furthermore, studies have shown that inhibiting PTP1B may also hold promise in diseases such as Alzheimer's disease and fatty liver disease, and may exert therapeutic effects in cancer by suppressing oncogenic signaling pathways. However, developing inhibitors with selectivity and oral bioavailability remains a major challenge due to the positively charged, highly conserved catalytic site of the PTP superfamily and its strong structural similarity to homologous PTPs. PTP1B degraders represent a novel therapeutic strategy that specifically eliminates intracellular PTP1B protein through targeted degradation mechanisms. This approach aims to overcome the "undruggable" limitations of traditional inhibitors and may offer potential treatment avenues for various PTP1B-related diseases. This review summarizes recently reported PTP1B inhibitors and degraders, including natural products, derivatives of natural products, synthetic small molecules, dual-target inhibitors, as well as advances in PTP1B degraders. It aims to provide a foundation for the rational design and further investigation of PTP1B inhibitors and degraders.},
}

@article {pmid41831271,
year = {2026},
author = {Muralidhar, D and Kumar, P},
title = {Positron emission tomography-based radiopharmaceuticals for imaging the expression and function of multidrug resistance P-glycoprotein.},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {393},
number = {4},
pages = {104307},
doi = {10.1016/j.jpet.2026.104307},
pmid = {41831271},
issn = {1521-0103},
abstract = {Multidrug resistance is a major reason for drug resistance in patients undergoing chemotherapy or other drug therapy. The overexpression of efflux proteins, such as multidrug resistance protein or P-glycoprotein (P-gp), has been recognized as a major cause of the drugs' efflux from the brain. P-gp expression is not only responsible for drug resistance, but underactivity leads to the accumulation of amyloid proteins and may become one of the reasons for Alzheimer disease. Hence, measuring the activity of the efflux proteins can indicate whether the candidate is suitable for chemotherapy. Therefore, several radiotracers have been developed to image P-gp activity. Positron emission tomography imaging can assess P-gp function and, therefore, plays a crucial role in informing clinicians' decisions to adjust treatment. This review article discusses advancements in radiopharmaceuticals for imaging P-gp function and expression, particularly at the blood-brain barrier. It highlights the significance of various radiolabeled tracers, including verapamil, metoclopramide, and MC225, in assessing P-gp-mediated drug delivery to the brain and its role in various neurodisorders. This article discusses the outcomes of various radiopharmaceuticals used in imaging P-gp expression and function. SIGNIFICANCE STATEMENT: This review article highlights the evolution of radiopharmaceuticals for imaging P-gp in various disorders, including drug resistance, Alzheimer disease, and epilepsy. P-gp imaging can play a crucial role in drug development and aid in identifying tumors that are responsive or resistant to chemotherapy. It may help clinicians decide whether a patient is suitable for chemotherapy. Positron emission tomography imaging can provide information on P-gp activity, which can be assessed before and during chemotherapy.},
}

@article {pmid41831326,
year = {2026},
author = {Furlan, R and Di Sapio, A and Ferraro, D and Rossi, E and Valentino, P and Terracciano, D},
title = {Translating neurofilament light chain testing into clinical practice: a multidisciplinary implementation roadmap.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {41831326},
issn = {1437-4331},
abstract = {Neurofilament light chain (NfL) has been identified as a sensitive and broadly validated biomarker of neuroaxonal injury across multiple neurological conditions, including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and atypical parkinsonian syndromes. This position paper provides a multidisciplinary roadmap for translating circulating NfL testing into routine clinical practice, integrating analytical, interpretative, and organizational dimensions. It summarizes the biological basis and clinical evidence supporting NfL as a diagnostic, prognostic, and monitoring tool, emphasizing its high sensitivity to neuroaxonal injury across both acute inflammatory and chronic degenerative processes. Comparative analysis of immunoassay technologies identifies strengths and critical sources of variability, while operational guidelines highlight the need for pre-analytical standardization, inter-laboratory harmonization, and participation in quality control schemes. Confounders such as age, BMI, renal function, and comorbidities are shown to significantly influence interpretation, supporting the use of age-adjusted Z-scores, percentiles, and longitudinal normalization for accurate patient-level evaluation. From a clinical standpoint, the paper focuses on practical indications for NfL testing in MS, recommending its use for disease activity prediction and monitoring, treatment decisions and treatment response assessment. Integration of blood NfL with magnetic resonance imaging (MRI), glial fibrillary acidic protein (GFAP) and other biomarkers measurement is proposed as a core strategy for biomarker-driven precision neurology. The authors outline an implementation model encompassing laboratory validation, structured reporting and alignment with national neurological care pathways. They conclude that the transition of NfL into clinical use requires harmonized analytical procedures, interdisciplinary education, and sustainable governance frameworks. Priority actions include regulatory qualification, establishment of international reference materials, and development of pragmatic real-world trials to consolidate its clinical utility. When these measures are achieved, NfL will represent a cornerstone biomarker for precision neurology and neurodegeneration monitoring.},
}

@article {pmid41831370,
year = {2026},
author = {Perry, R and Kipps, C and Martín, MES and Bozzali, M and Logroscino, G and Trafford, S and Dhadda, S and Kanekiyo, M and Goodwin, A and Hodgkinson, M and Hersch, S and Irizarry, M and Kramer, L and Froelich, L},
title = {Corrigendum to "Lecanemab for treatment of individuals with early Alzheimer's Disease (AD) who are apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes" [The Journal of Prevention of Alzheimer's Disease (2026) 100507].},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {4},
pages = {100527},
doi = {10.1016/j.tjpad.2026.100527},
pmid = {41831370},
issn = {2426-0266},
}

@article {pmid41831376,
year = {2026},
author = {Jacobson, M and Deuschle, C and Peneva, D and Wang, AN and Roache, C and Walsh, M and Ferrell, PB and Manetas, MA and Raman, R and Aisen, P and Goldman, D},
title = {Evaluating evidence-based recruitment strategies for Alzheimer's disease and related dementias clinical trial research: A literature review.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {5},
pages = {100532},
doi = {10.1016/j.tjpad.2026.100532},
pmid = {41831376},
issn = {2426-0266},
abstract = {BACKGROUND: With the prevalence of Alzheimer's disease and related dementias (ADRD) rising, prevention and treatment clinical trials are increasingly important. Yet inadequate participant recruitment to ADRD research-a leading cause of trial delays, suspensions, or discontinuations-continues to hinder innovation and increase costs. This literature review aimed to identify ADRD recruitment strategies that are effective and ineffective, based on quantitative outcomes, with the goal of optimizing recruitment and advancing recruitment science.

METHODS: PubMed, Google Scholar, relevant ADRD websites, and references were searched for studies meeting inclusion criteria-those reporting quantitative outcomes aimed at improving recruitment rates, timely recruitment, or representation. Reference lists from relevant systematic reviews and meta-analyses, including publications from leading researchers, were also examined. The Mixed Methods Appraisal Tool (MMAT) was used to assess evidence quality.

RESULTS: The search yielded 965 publications, of which 50 met inclusion criteria. Few studies reported recruitment methods for pharmacological trials, and many lacked sufficient detail or standardized reporting to assess quality using MMAT criteria, making it difficult to determine effectiveness. Recruitment efforts deemed successful by study authors often relied on multi-pronged approaches integrating community engagement, structured outreach, and digital tools. However, evidence for effective and scalable strategies remains limited.

CONCLUSION: Advancing ADRD recruitment science requires progress in two key areas: embedding recruitment evaluation directly into trial protocols and encouraging broader sharing of recruitment data. Routine practices, such as publishing recruitment outcomes and adopting standardized reporting, can help close the evidence gap. These approaches enable comparison, replication, and generalizability of effective strategies, ultimately accelerating progress in ADRD research.},
}

@article {pmid41832672,
year = {2026},
author = {Haddadi, A and Heidari, A and Rezaei, N},
title = {Alzheimer's Disease, Circadian Rhythms, and the Immune System: Potential Interconnections.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128433445251211165723},
pmid = {41832672},
issn = {1873-4286},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, marked by the accumulation of amyloid-β plaques and neurofibrillary tangles. Its incidence is rising as the global population ages. This narrative review explores the emerging interconnections among AD, circadian rhythms, and the immune system. The circadian system, governed by endogenous clocks, regulates key physiological processes and exhibits disruptions in the early stages of AD. Chronodisruption, disturbance of circadian rhythms, has been implicated in AD pathogenesis through its effects on metabolism, sleep, and neuroinflammation. The immune system also plays a central role in AD, with microglia and astrocytes contributing to disease progression. Immune function displays circadian variation, and disruptions in sleep and circadian timing may impair immune responses, promote inflammation, and compromise amyloid-β clearance. Therapeutic strategies targeting circadian regulation, including melatonin agonists and orexin receptor antagonists, may help mitigate cognitive decline. Additionally, the gut microbiome, modulated by circadian and sleep patterns, has emerged as a potential contributor to AD pathophysiology. This review also highlights interventions that support immune health, such as the Mediterranean diet, antiviral therapies, and physical activity, which may collectively attenuate AD risk. Finally, the bidirectional relationship between immune signaling and circadian rhythms, evidenced by immune modulation of clock genes, underscores a complex, integrated regulatory network. Understanding these interrelated systems may uncover novel approaches for prevention and treatment. By elucidating these interconnections, this review aims to shed light on novel therapeutic strategies and interventions that address multiple facets of the disease, offering potential avenues to improve outcomes for individuals with AD.},
}

@article {pmid41832727,
year = {2026},
author = {Sharma, M and Mazumder, R and Padhi, S and Shivangi, },
title = {Target-Based Drug Delivery Approaches against Alzheimer's Disease - Recent Updates.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266421105251206211422},
pmid = {41832727},
issn = {1873-4294},
abstract = {Millions of people worldwide suffer from Alzheimer's disease (AD), a crippling neurological illness. The ongoing rise of AD necessitates the rapid development of effective preventive and therapeutic approaches. Existing pharmacologic treatments for AD are divided into two categories: acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, both of which have numerous adverse effects and are largely ineffective in slowing disease progression. Current treatments for AD face challenges such as limited bioavailability and the difficulty of crossing the brain's protective barriers, known as the Blood-Brain Barrier (BBB). The side effects of these drugs include dizziness, elevated blood pressure, constipation, vomiting, and cramping of abdominal muscles. In this review, we focus on novel targets, including the Tau protein, M1 mAChR, and PDE4s, along with their intricate mechanisms of action in AD, which have shown promising outcomes in numerous studies for successful treatment. Additionally, we discuss synthetic and herbal medications that act on these novel targets, including orthosteric agonists, allosteric compounds, and positive allosteric modulators (PAMs) of M1 mAChR, as well as taubased natural products as AD therapeutics. Examples include the microtubule stabilizer paclitaxel from the Pacific Yew Taxus brevifolia and the anti-amyloid agent curcumin, isolated from turmeric. The role of PDE4 in the coordination of cAMP response element-binding signaling in AD is also covered in this review. We highlight the advantages of specifically targeting PDE4D and discuss the use of herbal medications such as resveratrol, curcumin, 6-gingerol, and capsaicin, which are effective AD therapeutics and potential PDE4D inhibitors.},
}

@article {pmid41833033,
year = {2026},
author = {Mallick, K and Ruwatia, R and Mondal, AC and Banerjee, S},
title = {Neurosteroids in Neurological and Psychiatric Disorders: Therapeutic Implications.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273411580251203115939},
pmid = {41833033},
issn = {1996-3181},
abstract = {Neurosteroids play a significant role in brain functions with substantial implications for mood regulation, seizure susceptibility, stress response, and potential therapeutic applications. However, dysregulation of steroidogenesis and its signalling is associated with various neurological and psychiatric disorders, such as major depressive disorder, schizophrenia, tourette syndrome and post-traumatic stress disorder, with altered levels of neuroactive steroids contributing to these conditions. Neurosteroids can counteract the effects of stress by enhancing GABAergic inhibition, thereby helping to maintain emotional homeostasis. Furthermore, neuroinflammatory processes linked to neurodegenerative diseases, including Alzheimer's and Parkinson's, can disrupt neurosteroid synthesis. The potential for therapeutic modulation of neurosteroid biosynthesis via ligands targeting steroidogenic pathways offers an exciting avenue for treatment. Despite the promise of neuroactive steroids, their rapid metabolism and low oral bioavailability pose significant challenges. Consequently, extensive research is now focused on developing synthetic analogues and modulators that can modulate neuroactive steroid synthesis and metabolism. This review is based on an understanding of neuroactive steroids and their role in neurological disorders.},
}

@article {pmid41833049,
year = {2026},
author = {Yanchao, L and Yuchen, L and Huan, X and Yuyan, G and Junfei, Z and Roumiantsev, S and Mashkin, A and Beylerli, O and Gareev, I and Sibin, Z and Yang, G},
title = {Immune Cell Infiltration and Key Gene Identification in Alzheimer's Disease and Sleep Deprivation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273402581251127144625},
pmid = {41833049},
issn = {1996-3181},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by Amyloid-β plaques and neurofibrillary tangles. Disrupted circadian rhythms are common in AD and may worsen cognitive decline and psychological symptoms. The link between sleep deprivation and Alzheimer's risk remains unclear. This study aimed to identify potential diagnostic markers for Alzheimer's and sleep deprivation, focusing on the role of immune cell infiltration in disease progression.

MATERIALS AND METHODS: We examined AD expression data from the GEO database and sleep deprivation(SD)-related data from GeneCards. Using LIMMA on the GSE15222 dataset, we found 209 DEGs, analyzed them with four machine learning algorithms, and identified four Hub genes. We validated these findings with the GSE33000 dataset. CIBERSORT was employed to analyze 22 immune cell features, and Spearman correlation was used to assess the link between diagnostic markers and immune cells.

RESULTS: AD and SD were linked to immune microenvironment changes. Initially, 1568 potential key genes were identified, and Venn analysis revealed 209 overlapping regions. Machine learning validated four key genes, confirming their high predictive accuracy. Significant differences in immune cell expression were found in AD samples, and correlation analysis showed CIT, FASN, ELK1, and GFAP were significantly associated with various immune cells.

CONCLUSION: CIT, FASN, ELK1, and GFAP are key genes linked to pathology progression in AD and SD within the immune microenvironment. Identifying molecular subgroups may offer new perspectives for personalized Alzheimer's treatment.},
}

@article {pmid41833051,
year = {2026},
author = {Thorat, DS and Uddin, MJ and Hag Ibrahim, RI and Oladosu, TA and Sahu, KK and Chidrawar, VR and Singh, S and Nagime, PV and Basu, B and Shafi, S},
title = {Reconnoitering the Potential of the Pharmacogenomics Approach in the Management of Alzheimer's Disease: A Review.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273388245251113054232},
pmid = {41833051},
issn = {1996-3181},
abstract = {Alzheimer's disease (AD) is a neurological disorder that affects adults worldwide. AD is also an essential geriatric disorder because of its significant emotional and economic impact on individuals, their loved ones, and society. Traditional treatments do not account for the genetic heterogeneity among patients, leading to variable therapeutic effects. Pharmacogenomics customizes medicinal therapies based on a person's genetic profile, enhances efficacy, and minimizes side effects. This review examines how genetic variables affect responses to drugs in neurodegenerative illnesses and the potential for pharmacogenomics to improve treatment. This review explores the possibility of pharmacogenomics in clinical practice, including ethical and data integration concerns. Furthermore, this review discusses the hypothesis of the effects of mutant presenilin on AD therapeutics, along with several clinical trial drugs, their effects, and possible treatment opportunities. Additionally, this review provides insights into prospects and potential treatment strategies for AD. The use of pharmacogenetic/pharmacogenomic procedures in AD studies and clinical trials can help generate cost-effective medications while also increasing therapeutic safety and efficacy.},
}

@article {pmid41833245,
year = {2026},
author = {Rajkumar, M and Kirubakaran, D and Govindaraj, P and Shanmugarathinam, A and Deepak, P and Rajkumar, P and Uvarajan, D and Uddandrao, VVS and Manikandan, R and Balamurugan, P},
title = {Recent advances in polymeric nanoparticle-mediated drug delivery system across the blood-brain barrier in Alzheimer's disease.},
journal = {Colloids and surfaces. B, Biointerfaces},
volume = {263},
number = {},
pages = {115612},
doi = {10.1016/j.colsurfb.2026.115612},
pmid = {41833245},
issn = {1873-4367},
abstract = {Alzheimer's disease (AD) is driven by complex and interrelated pathological processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, synaptic loss, and chronic neuroinflammation. These multifactorial mechanisms contribute to progressive cognitive decline and limit the effectiveness of conventional therapeutic strategies. Polymeric nanoparticles (PNPs) have emerged as a promising nanotechnological platform for targeted drug delivery in AD, addressing key challenges such as inadequate blood-brain barrier (BBB) permeability, rapid enzymatic degradation of therapeutic molecules, and poor pharmacokinetics. PNPs improve therapeutic efficacy by enabling controlled and sustained drug release, enhancing molecular stability, and promoting selective accumulation in affected brain regions. PNPs can modulate multiple molecular events that underlie AD pathogenesis. They inhibit Aβ fibrillation, reduce tau phosphorylation, scavenge reactive oxygen species (ROS), suppress neuroinflammatory signalling, activate Nrf2-driven antioxidant defense, and regulate microglial polarization toward a neuroprotective phenotype. Additionally, PNPs provide an efficient delivery system for diverse therapeutic agents, including small molecules, peptides, antioxidants, nucleic acids, and natural compounds, which often face challenges in BBB penetration and systemic stability. Recent innovations in surface engineering, biodegradable polymer chemistry, gene-responsive nanocarriers, and stimuli-responsive release systems have further enhanced the potential of PNPs as disease-modifying interventions. Despite these significant advancements, key limitations remain, including uncertainties regarding long-term biosafety, inconsistent biodistribution, challenges in nanoparticle clearance, and translational gaps between preclinical models and humans with AD. Addressing these issues will require interdisciplinary collaboration among materials science, neurobiology, pharmaceutical technology, and clinical research. Overall, this review highlights recent progress, therapeutic mechanisms, and the growing promise of PNP-based brain-targeted nanomedicine as a transformative approach for AD treatment.},
}

@article {pmid41833767,
year = {2026},
author = {Guo, Y and Li, X and Chen, Y and Li, Y and Cheng, Q and Jiang, Y and Tian, S and Yuan, B and Liu, Y and Hu, H and Li, S},
title = {Sarsasapogenin ameliorates Alzheimer's disease by dual inhibition of RIPK1-mediated necroptosis and pyroptosis.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112481},
doi = {10.1016/j.cellsig.2026.112481},
pmid = {41833767},
issn = {1873-3913},
abstract = {Sarsasapogenin (Sar), a natural bioactive steroidal saponin derived from Anemarrhena asphodeloides, has demonstrated significant neuroprotective effects in preclinical models of Alzheimer's disease (AD). However, its specific mechanism of action, particularly in modulating receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis and pyroptosis, remains underexplored. This study aimed to investigate Sar's therapeutic potential in AD by targeting RIPK1, a central regulator of programmed cell death. We employed biolayer interferometry (BLI), cellular thermal shift assays (CETSA), and drug affinity responsive target stability (DARTS) to confirm the binding of Sar to RIPK1. In vitro, we assessed the effects of Sar on RIPK1 activation, necroptosis, and pyroptosis in SH-SY5Y neuroblastoma and BV2 microglial cells using Western blotting, immunofluorescence, and cytokine assays. In vivo, the therapeutic efficacy of Sar was evaluated in the 5 × FAD transgenic mouse model, with behavioral analysis (Morris water maze) and histological assessments of brain tissue pathology. Sar demonstrated robust binding to RIPK1 (KD = 435 nM), enhancing its thermal stability and resistance to proteolytic degradation. Treatment with Sar significantly inhibited RIPK1 phosphorylation and downstream necroptotic and pyroptotic signaling in neurons and microglia. In the 5 × FAD mouse model, Sar markedly improved spatial memory performance, reduced amyloid-beta (Aβ) plaque deposition, and decreased neuroinflammatory and necroptotic markers in both the cortex and hippocampus. Sar is a promising natural RIPK1 inhibitor capable of concurrently mitigating both necroptosis and pyroptosis-two critical pathological processes underlying AD. These findings suggest that Sar may serve as a novel disease-modifying therapeutic for AD by regulating multiple pathways involved in neurodegeneration, offering new insights into the potential of natural products in AD treatment.},
}

@article {pmid41834394,
year = {2026},
author = {Yuan, M and Zhou, HY},
title = {CTAD 2025: Key trends redefining therapeutic and diagnostic strategies in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430764},
doi = {10.1177/13872877261430764},
pmid = {41834394},
issn = {1875-8908},
abstract = {This article synthesizes key themes emerging from the CTAD 2025 meeting, highlighting significant advances in Alzheimer's disease (AD) research and clinical practice. New disease-modifying approaches-ranging from next-generation anti-amyloid-β and anti-tau antibodies to small-molecule aggregation inhibitors and gene-based strategies-underscore a growing shift toward multi-target therapeutic frameworks. Blood-based biomarkers, such as p-tau217, p-tau181, glial fibrillary acidic protein, and neurofilament light, are nearing clinical readiness, while digital biomarkers and wearable technologies are enabling remote, continuous assessment of cognitive and physiological functions. Clinical trial design is increasingly oriented toward earlier disease stages and genetically or biomarker-defined high-risk groups, incorporating adaptive methodologies and real-world data to enhance efficiency and generalizability. Collectively, these developments signal an impending transition over the next two to three years from a centralized, cognitive scale-driven model of AD care to a more decentralized, biomarker-guided precision paradigm. CTAD 2025 thus marks a pivotal inflection point in the evolving structure of AD diagnosis and treatment.},
}

@article {pmid41834402,
year = {2026},
author = {Al-Hammadi, M and Fleyeh, H and Thomas, I},
title = {Gait and movement analysis for discrimination between people with dementia and healthy control persons based on pose estimation and machine learning.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430001},
doi = {10.1177/13872877261430001},
pmid = {41834402},
issn = {1875-8908},
abstract = {BackgroundDementia disorders are affecting millions of people globally, characterized by memory loss, communication difficulties, and motor function decline. Accurate and early dementia detection is crucial for effective management and treatment. Gait analysis offers a non-invasive method for dementia detection by identifying subtle changes in walking patterns that often precede cognitive symptoms.ObjectiveThis study aims to evaluate the clinical utility of video-based gait analysis using the Timed Up and Go (TUG) test under single and dual-task conditions (TUGdt) for distinguishing individuals with dementia disorders from healthy controls (HCs).MethodThe study implemented three machine learning models: Support Vector Machine (SVM), Logistic Regression (LR), and Random Forest (RF), to discriminate between persons with dementia and HCs. The dataset consists of a cohort of 64 people with dementia (47 with Alzheimer's disease) and 67 HCs. The participants performed the TUG test as a single and dual-task (TUGdt). In the TUGdt, participants performed the TUG test while simultaneously completing an additional cognitive task (i.e., animal naming (TUGdt-NA) or reciting months in reverse order (TUGdt-MB)).ResultsThe results showed that dual-task classification outperformed the single-task. The SVM algorithm achieved the highest accuracy in the TUGdt-NA task (accuracy of 87% ± 5.1 and recall of 86.6% ± 3.2) using 5-fold cross-validation and accuracy of 85.5% and recall of 89.5% using Leave-One-Out Cross-Validation (LOOCV) in the TUGdt-MB task.ConclusionsIn summary, video-based gait features effectively distinguish people with dementia from HCs, particularly under dual-tasking, offering cost-effective, automated, and non-invasive pre-screening to complement clinical assessments.},
}

@article {pmid41834411,
year = {2026},
author = {Yue, J and Carriquiriborde, V and Cheng, WH and Yildirim, T and Fan, J and Tok, S and Kelly, ML and Wellington, CL and Kent, BA},
title = {Repetitive Mild Traumatic Brain Injury Causes Neuronal Damage in the APP/PS1 Mouse Model of Alzheimer's Disease Without an Enduring Impact on Amyloid Pathology, Sleep, or Epileptiform Activity.},
journal = {Journal of neurotrauma},
volume = {},
number = {},
pages = {8977151261430301},
doi = {10.1177/08977151261430301},
pmid = {41834411},
issn = {1557-9042},
abstract = {Traumatic brain injury (TBI) is a known risk factor for Alzheimer's disease and related neurodegenerative diseases. Sleep disturbances and epileptiform abnormalities can appear after TBI and may contribute to the development of neuropathology. In this study, we characterized sleep, epileptiform activity, and neuropathology after repetitive mild traumatic brain injury (rmTBI) in a mouse model of Alzheimer's disease. We used the Closed Head Impact Model of Engineered Rotational Acceleration to deliver rmTBI or sham (control) treatment to 6-month-old APP/PS1 mice (N = 19). One month post-injury, we implanted electroencephalogram and electromyographic electrodes, recorded for 72 h, and then collected brain tissue and blood plasma. Our assessment of sleep architecture showed that time spent in vigilance state was not affected by the rmTBI 1 month post-injury; however, power spectra analysis showed a shift toward higher frequencies in the rmTBI group during non-rapid eye movement sleep. Epileptiform activity did not differ between sham and rmTBI. Compared with sham controls, the rmTBI group showed higher neurofilament light (NF-L), but not glial fibrillary acidic protein in blood plasma and no change in Aβ pathology. These results indicate sustained neurological injury in the APP/PS1 mice 1 month after rmTBI without affecting amyloid deposition in the brain. Our study suggests that rmTBI can induce neural injury without causing enduring sleep disruption, seizures, and exacerbation of amyloidosis in the APP/PS1 mouse model.},
}

@article {pmid41834587,
year = {2026},
author = {Shimizu, K and Yasuda, S and Maeshima, H and Ichikawa, T and Baba, H},
title = {Serum Amyloid β Oligomer May Predict Treatment Response in Middle-Aged and Late-Life Patients With Depression.},
journal = {Neuropsychopharmacology reports},
volume = {46},
number = {2},
pages = {e70109},
doi = {10.1002/npr2.70109},
pmid = {41834587},
issn = {2574-173X},
mesh = {Humans ; Male ; Female ; *Amyloid beta-Peptides/blood ; Middle Aged ; Aged ; *Antidepressive Agents/therapeutic use ; *Major Depressive Disorder/drug therapy/blood ; *Peptide Fragments/blood ; Treatment Outcome ; Biomarkers/blood ; Adult ; Aged, 80 and over ; },
abstract = {AIM: Late-life patients with depression are reportedly less responsive to antidepressant treatment than younger patients. Additionally, patients who have depression comorbid with Alzheimer's disease (AD) and those with an amyloid β (Aβ) burden have shown a poor response to antidepressant treatment, suggesting that AD pathology may contribute to treatment resistance. A recent report indicated that Aβ oligomers in blood have increased in patients with AD and are associated with AD pathology. This study was performed to reveal the relationship between blood Aβ oligomers and the response to antidepressant treatment in middle-aged and late-life patients with depression.

METHODS: In this observational study, serum levels of Aβ40, Aβ42, and Aβ oligomers were evaluated in 80 inpatients with major depressive disorder aged ≥ 40 years. Depressive symptoms were assessed at admission (baseline) and after 4 weeks of treatment.

RESULTS: There were significantly fewer treatment responders among patients with than without serum Aβ oligomers (p = 0.016). Serum Aβ oligomers were found to influence the treatment response even after control for age, sex, number of depressive episodes, severity of depression, and Mini-Mental State Examination scores (p = 0.031).

CONCLUSIONS: These results suggest that serum Aβ oligomers may predict a poor response to antidepressant treatment in middle-aged and late-life patients with depression. Our findings also lead us to speculate that elderly patients with a poor treatment response may share AD-related pathophysiological features or neural vulnerability.},
}

Humans
Male
Female
*Amyloid beta-Peptides/blood
Middle Aged
Aged
*Antidepressive Agents/therapeutic use
*Major Depressive Disorder/drug therapy/blood
*Peptide Fragments/blood
Treatment Outcome
Biomarkers/blood
Adult
Aged, 80 and over

@article {pmid41834979,
year = {2026},
author = {Li, Y and Chen, Y and Chen, S and Huang, X},
title = {[Aging-Associated Oral Microbiota Dysbiosis and Hypofunction: Their Role in Alzheimer's Disease Pathogenesis].},
journal = {Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition},
volume = {57},
number = {1},
pages = {56-64},
pmid = {41834979},
issn = {1672-173X},
mesh = {Humans ; *Alzheimer Disease/microbiology/etiology/physiopathology ; *Dysbiosis/complications/microbiology ; *Mouth/microbiology/physiopathology ; *Aging/physiology ; *Microbiota ; Amyloid beta-Peptides/metabolism ; Brain ; },
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative condition, imposes a major burden on societies with aging populations. Recent research indicates that oral cavity health is a critical factor influencing AD pathology, making proactive investigation of this modifiable risk factor essential. This review proposes that aging-related oral microecological dysbiosis and oral hypofunction may promote AD progression by inducing or exacerbating systemic inflammation and disrupting the homeostasis of the "oral-gut-brain" axis. Moreover, each factor may worsen damage through distinct biological pathways: oral microbiota dysbiosis allows direct invasion of the central nervous system by oral pathogens, promoting amyloid β-protein (Aβ) deposition and Tau hyperphosphorylation, while chronic sensory deprivation from oral dysfunction triggers neuronal degeneration and adverse remodeling in key cognitive brain regions. This review aims to systematically elucidate the roles of oral microbiota dysbiosis and oral hypofunction in AD pathogenesis in the context of aging, clarify their underlying biological mechanisms, and explore the potential value of integrating oral cavity health management into comprehensive AD prevention and treatment strategies.},
}

Humans
*Alzheimer Disease/microbiology/etiology/physiopathology
*Dysbiosis/complications/microbiology
*Mouth/microbiology/physiopathology
*Aging/physiology
*Microbiota
Amyloid beta-Peptides/metabolism
Brain

@article {pmid41835065,
year = {2026},
author = {Xiao, X and Yan, X and Liang, C and Yang, Y},
title = {Metabolic dysfunction and mitochondrial failure in Alzheimer's disease: integrating pathophysiology, clinical evidence and emerging interventions.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1772036},
pmid = {41835065},
issn = {1664-2295},
abstract = {Alzheimer's disease (AD) is a gradual and irreversible decline in the brain's ability to function which is not only signified by amyloid-beta plaques and neurofibrillary tangles but also by and metabolic and mitochondrial changes that have a negative impact on the classical neuropathological hallmarks. It is becoming increasingly clear that the central roles in the process of synaptic dysfunction, neuronal death and cognitive decline are played by the brain's impaired glucose utilization, insulin resistance, lipid metabolism alterations, and energy homeostasis disruption. Mitochondrial dysfunctions in AD comprising of oxidative phosphorylation defects, ATP production decrease, reactive oxygen species generation over and above the normal level, poor mitochondrial dynamics, and vacuolar-type H+-ATPase-mediated cell death are the factors that further worsen the situation and hence speed up the process of neuronal death and eventually, disease progression. The metabolic and mitochondrial disturbances have a two-way relationship with amyloid-beta and tau pathology, neuroinflammation, and oxidative stress, thus creating a self-sustaining cycle of neurodegeneration. Besides, clinical and neuroimaging studies, fluorodeoxyglucose positron emission tomography, cerebrospinal fluid biomarkers, and peripheral metabolic profiling all support the notion that metabolic impairment is an early and clinically relevant feature of AD very convincingly. Thus, the attention of the scientific community has turned more and more toward the approaches that use the metabolic and mitochondrial pathways as their target. The new treatments are coming, including insulin sensitizers, ketogenic and Mediterranean diets, mitochondrial-targeted antioxidants, exercise, metabolic modulators, and new drugs, all aimed at bringing back equilibrium to bioenergetics and letting neurons live longer. In this review, we have considered the current mechanistic insights, clinical evidence, and therapeutic advances related to metabolic dysfunction and mitochondrial failure in AD together and their potential as early biomarkers and modifiable targets for disease prevention and treatment that are highlighted.},
}

@article {pmid41836011,
year = {2026},
author = {Chakif, D and Furrer, J},
title = {The impact of nutritional, environmental, and lifestyle factors on neurological disorders: therapeutic implications and mechanistic insights.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1765786},
doi = {10.3389/fphar.2026.1765786},
pmid = {41836011},
issn = {1663-9812},
abstract = {Neurological disorders like Alzheimer's, Parkinson's, multiple sclerosis, and primary psychiatric conditions are complex, arising from a mix of genetic and modifiable risks. Growing evidence indicates that nutrition, environment, and lifestyle significantly influence disease development, progression, and treatment response. Nutrients such as vitamins, minerals, omega-3 fatty acids, and polyphenols affect neuroinflammation, oxidative stress, mitochondrial health, and neurotransmitter function. Dietary patterns like the Mediterranean and ketogenic diets offer protective benefits in clinical and experimental contexts. Meanwhile, environmental neurotoxicants-air pollution, heavy metals, pesticides, and endocrine disruptors contribute to neurodegeneration via oxidative damage, synaptic impairment, and epigenetic alterations. Lifestyle factors, such as physical activity, sleep, stress, and substance use, affect brain plasticity, neurogenesis, and metabolic health, thereby influencing disease progression over time. These factors often share common pathways such as oxidative stress, inflammation, vascular injury, mitochondrial dysfunction, and protein misfolding, underscoring the need for a comprehensive prevention and treatment strategy. Emerging therapies now incorporate personalized nutrition, lifestyle changes, and environmental risk mitigation alongside traditional drugs, supported by advances in multi-omics, digital health, and systems biology. Public health efforts to reduce neurotoxic exposure and encourage healthy habits further strengthen these approaches. This review summarizes existing mechanistic and clinical knowledge, with a focus on the potential of nutritional, environmental, and lifestyle interventions in neurological diseases. It also outlines the future research required to enhance precision neurology and strategies for brain health prevention.},
}

@article {pmid41836026,
year = {2026},
author = {Zhao, M and Qu, Y and Zhang, S and Zhang, M and Wang, H and Yang, Y and Xue, G and Hou, X and Yan, X},
title = {Multi-target intervention mechanisms and prospects of the traditional Chinese medicine Scutellaria baicalensis georgi in Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1707688},
doi = {10.3389/fphar.2026.1707688},
pmid = {41836026},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is one of the most prevalent central nervous system disorders affecting middle-aged and elderly populations. As a neurodegenerative disease, its primary clinical manifestations include memory impairment, cognitive dysfunction, and behavioral abnormalities. However, there are limited clinically available treatments for AD. Existing medications neither cure the disease nor halt its progression, and are often associated with significant side effects. Scutellaria baicalensis Georgi, with its long history of medicinal use, shows potential for treating central nervous system disorders. Modern pharmacological research has revealed its antioxidant, anti-inflammatory, antiviral, neuroprotective, and immunomodulatory properties. Its active metabolites, such as baicalin and baicalein, exert multi-target effects by simultaneously influencing Aβ production and aggregation, tau phosphorylation, and microglial activation, while also regulating brain-gut axis function. This systematic review examines the mechanisms of action of baicalin and baicalein, the active metabolites of Scutellaria baicalensis Georgi, in treating Alzheimer's disease, offering novel insights and research directions for modern medical approaches to Alzheimer's disease treatment.},
}

@article {pmid41836505,
year = {2026},
author = {Ma, T and Jester, H and Wang, X and Li, T and Suhocki, A and Zhou, X and Proud, C and Rosenblum, K},
title = {Suppression of neuronal eEF2K alleviates cognitive deficits and apathy-like behavior in APP/PS1 AD model mice.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-8970895/v1},
pmid = {41836505},
issn = {2693-5015},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by synaptic failure, cognitive impairment and neuropsychiatric symptoms (NPS). Apathy is the most common NPS seen in AD patients, and its underlying mechanisms remain unknown. Here, we investigated the roles of neuronal eukaryotic elongation factor 2 (eEF2) phosphorylation (by its kinase eEF2K) in AD-associated cognitive deficits and NPS. We performed a series of experiments using a multidisciplinary approach including genetics, behavioral assays, synaptic electrophysiology, and unbiased proteomics. The results demonstrated that neuron-specific inhibition of eEF2K and eEF2 phosphorylation can alleviate cognitive deficits, synaptic plasticity impairments, and apathy-like behavior in aged APP/PS1 AD model mice. Our findings indicate the therapeutic potential of targeting the eEF2K signaling in the treatment of dementia and NPS in AD and related dementias (ADRDs).},
}

@article {pmid41836522,
year = {2026},
author = {Liu, A and Xing, L and Li, J and Yao, M and Song, J and Guo, W and Duan, P and Li, H},
title = {Traditional Chinese Medicine and Ferroptosis in Alzheimer's Disease: A Potential Therapeutic Approach.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {590868},
doi = {10.2147/DDDT.S590868},
pmid = {41836522},
issn = {1177-8881},
mesh = {*Ferroptosis/drug effects ; Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Medicine, Chinese Traditional ; *Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use ; Animals ; },
abstract = {Alzheimer's disease (AD) represents a prevalent neurodegenerative disorder associated with considerable morbidity and mortality. Currently, no therapeutic agents exist that can achieve a fundamental reversal or complete cure for this condition. Consequently, the identification of novel molecular targets and the development of innovative treatment modalities aimed at slowing progression and alleviating symptoms represent pressing priorities within AD clinical research. Ferroptosis, a regulated cell death process driven by intracellular iron dysregulation and excessive lipid peroxidation, is now recognized as a critical contributor to AD pathogenesis. Traditional Chinese medicine (TCM) has demonstrated beneficial outcomes in managing AD, and emerging evidence suggests its regulatory effects may extend to modulating ferroptotic pathways. This review summarizes and analyzes the therapeutic efficacy of various TCM strategies against AD, including herbal extracts, monomers (eg, alkaloids, terpenoids, glycosides, phenolic derivatives, quinones), compound formulas, and acupuncture. It highlights how these interventions target key ferroptosis-related axes-such as iron homeostasis, the system Xc-/GSH/GPX4 antioxidant system, and the Keap1/Nrf2/ARE pathway-to collectively address the pathological foundation of the disease. However, current evidence is predominantly preclinical, and the translational potential of TCM is constrained by challenges including blood-brain barrier penetration, pharmacokinetic profiles, standardization, and safety assessments. In conclusion, TCM exhibits substantial potential for both research and clinical application in AD by targeting and attenuating the ferroptosis pathway, offering promising avenues for disease modification and symptomatic relief.},
}

*Ferroptosis/drug effects
Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Medicine, Chinese Traditional
*Drugs, Chinese Herbal/pharmacology/chemistry/therapeutic use
Animals

@article {pmid41837371,
year = {2026},
author = {Ackley, SF and La Joie, R and Caunca, M and Mukherjee, S and Choi, SE and Trittschuh, EH and Crane, PK and Hayes-Larson, E and , },
title = {Substituting Blood-Based Biomarkers for Imaging Measures in Alzheimer's Disease Studies: Implications for Sample Size and Bias.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag068},
pmid = {41837371},
issn = {1758-535X},
abstract = {BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) pathology are appealing options in large population-based studies due to their low cost, minimal invasiveness, and feasibility of collection in non-clinical settings. Despite these benefits, blood-based biomarkers have lower test-retest reliability than neuroimaging measures like amyloid positron emission tomography (amyloid-PET) Centiloids; trade-offs in power and bias remain unexplored.

METHODS: We use data from Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) studies, which include both amyloid-PET and blood-based measures, to assess differences in statistical power, required sample size, and bias when replacing a neuroimaging measure with a blood-based measure. We use simulations parameterized based on these studies to show potential implications of using plasma p-tau 181 or p-tau 217, blood-based AD biomarkers, in place of Centiloids from amyloid-PET, when the biomarker is either the exposure or the outcome in an analysis of interest.

RESULTS: We demonstrated that substituting amyloid-PET Centiloids with a blood-based measure of p-tau can substantially reduce power, requiring 1.5 to 6.5 times the sample size to achieve 80% power compared to amyloid-PET. In addition, using a blood-based biomarker as the exposure can introduce significant regression dilution bias, attenuating estimated associations.

CONCLUSIONS: While blood-based biomarkers are lower cost and easier to collect than neuroimaging measures, their use as proxies for AD pathology may introduce substantial methodological challenges, depending on the p-tau isoform. Consideration of the sample sizes they necessitate and their potential for bias is critical for the design and interpretation of studies employing these biomarkers.},
}

@article {pmid41837374,
year = {2026},
author = {Kaufmann, CN and Yang, KH and Tseng, CI and Chang, G and Amjad, H and Albrecht, JS and Spira, AP and Gross, AL and Wickwire, EM and Malhotra, A},
title = {Using Observational Data to Investigate Cognitive Outcomes of Obstructive Sleep Apnea Treatment: A Scoping Review.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag078},
pmid = {41837374},
issn = {1758-535X},
abstract = {BACKGROUND: Prior research indicates a connection between obstructive sleep apnea (OSA) and cognitive deficits, prompting interest in whether OSA treatment can prevent or slow cognitive decline. Past clinical trials on OSA treatment and cognitive impairment have shown inconsistent results. However, observational data might help by examining more diverse populations and larger sample sizes, increasing the ability to detect subtle effects. Therefore, we reviewed literature to characterize studies evaluating cognitive outcomes from OSA treatment using observational study data.

METHODS: We conducted a scoping review of studies retrieved on PubMed and Embase. Studies were screened by title/abstract, and then full text, for inclusion. We extracted data characterizing data source, study design, population, sample size, follow-up time, treatments assessed, cognitive outcome variables, and key associations.

RESULTS: Of 3,655 unique articles obtained from PubMed and Embase, 13 met eligibility criteria. All were retrospective cohort studies. Ten studies evaluated positive airway pressure (PAP) therapies, one examined uvulopalatopharyngoplasty, and two evaluated any type of OSA treatment. No studies evaluated mandibular advancement devices. Cognitive outcomes assessed included dementia diagnosis (8 studies), and changes in cognitive performance (5 studies). Results from studies for most part found OSA treatment was associated with better cognitive outcomes, although effects varied in magnitude and statistical significance based on the data source, outcomes, and sample size.

CONCLUSIONS: Observational data has the potential to help evaluate cognitive outcomes from OSA treatment, but more studies are needed, especially for OSA therapies beyond PAP alone.},
}

@article {pmid41837520,
year = {2026},
author = {Zhao, Y and Lei, J and Wang, Z and Yang, S and Zhao, Z and Xie, Y and Ran, J and Zang, G},
title = {Identification of novel biomarkers for Alzheimer's disease: A deep learning omics-based approach to drug pair discovery and exploration of potential therapeutic targets.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00989},
pmid = {41837520},
issn = {1673-5374},
abstract = {The understanding of Alzheimer's disease is shifting from a traditional focus on Aβ/tau pathology to an emerging consensus that positions immune dysregulation as a central synergistic driver in the early stages of the disease. However, the causal relationships between peripheral immune cells, plasma proteins, and Alzheimer's disease, as well as the mediating effects of plasma proteins on the disease, remain poorly understood. Moreover, there are no effective drug combination therapies targeting plasma proteins for Alzheimer's disease. This study investigated the causal associations between immune cells, plasma proteins, and Alzheimer's disease, with a focus on the role of Fc gamma receptor 3A in disease progression. Using a two-sample Mendelian randomization approach, we identified 59 plasma proteins and 65 immune cell types significantly associated with Alzheimer's disease. We performed data mining of a large Alzheimer's disease cohort and drug databases and established a biofactor-regulated neural network for rapidly screening and optimizing compound drug pairs. Among the immune cells, CD8+ T cells, particularly CD8+CD28+CD45RA. T cells, were found to have a protective effect against Alzheimer's disease. Furthermore, increased expression of Fc gamma receptor 3A (also known as CD16a, an activating receptors of NK cells) in plasma and the hippocampus correlated with enhanced CD8+ T-cell infiltration and accelerated Alzheimer's disease progression in 5×FAD mice. Mediation analysis revealed that Fc gamma receptor 3A mediates the effects of CD8+ T cells on Alzheimer's disease risk. Additionally, Fc gamma receptor 3A gene expression levels were significantly higher in patients with Alzheimer's disease compared with individuals with mild cognitive impairment and cognitively normal participants, as revealed by an analysis of the Alzheimer's Disease Neuroimaging Initiative database. These findings suggest that CD8+ T-cell infiltration and Fcγ receptor 3A expression play critical roles in the pathophysiology of Alzheimer's disease and may serve as therapeutic targets. Molecular docking analysis further identified 19 candidate drugs targeting Fcγ receptor 3A. This study proposes novel immune-based therapeutic strategies and introduces an omics-based intelligent drug discovery framework for repurposing existing drugs for the treatment of complex diseases. The key contributions of this study include the identification of potential immune-based therapeutic targets for Alzheimer's disease and demonstration of the utility of bioinformatics and drug repurposing approaches in addressing complex neurodegenerative diseases.},
}

@article {pmid41837598,
year = {2026},
author = {Ma, J and Liu, T and Liu, FZ and Shi, YJ},
title = {Mechanistic Insights into the Qingge Formula for the Treatment of Alzheimer's Disease: A Network Pharmacology and Molecular Docking Study.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128403988251202073700},
pmid = {41837598},
issn = {1873-4286},
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects millions globally. This study explores the therapeutic mechanisms of Qingge Formula (QGF) against AD using network pharmacology and molecular docking.

METHODS: Active components and targets were identified via TCMSP, Swiss ADME, and GeneCards databases. PPI networks, GO, and KEGG analyses were performed, followed by molecular docking.

RESULTS: Core targets included PTGS2, EGFR, ESR1, STAT3, and SRC. GO identified 222 terms; KEGG revealed 65 pathways. Molecular docking revealed that the six key components bind to the core targets with energetically favorable conformations, among which SRC showed the highest affinity for all the Discussion: QGF likely modulates neuroinflammation, immunity, and synaptic plasticity pathways, with SRC as a crucial target.

CONCLUSION: QGF demonstrates multi-component, multi-target therapeutic potential against AD.},
}

@article {pmid41837602,
year = {2026},
author = {Onuki, K and Nishio, Y},
title = {Assessing professional caregiver burden related to patient agitation in dementia: A systematic review of measurement scales.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261430767},
doi = {10.1177/13872877261430767},
pmid = {41837602},
issn = {1875-8908},
abstract = {BackgroundAgitation is a common behavioral and psychological symptom of dementia that places significant burden on caregivers. While its impact on family caregivers is well-documented, its effect on professional caregivers remains underexplored. Additionally, it is unclear whether existing caregiver burden scales adequately capture the International Psychogeriatric Association's (IPA) definition of agitation. Since agitation requires different treatment approaches than cognitive impairment, its distinct burden warrants further investigation.ObjectiveThis systematic review examined scales used to assess professional caregiver burden related to agitation in dementia.MethodsFollowing PRISMA guidelines, we searched MEDLINE, Embase, and ICHUSHI for English and Japanese articles published during January 1980-August 2024. Studies included professional caregivers, either exclusively or alongside informal caregivers. Key outcomes were the number and frequency of scales, target population, and agitation coverage within the scales.ResultsWe identified 52 articles: 22 focused exclusively on professional caregivers, and 30 included both types. Publications involving both caregiver types increased notably in the last decade. Across studies, 39 scales were used. The Zarit Burden Interview (n = 21) and Neuropsychiatric Inventory (n = 15) were most frequent. Sixteen scales targeted the general population; 11 each were designed for professional and informal caregivers, and one for both. Most scales did not fully reflect the IPA's definition of agitation. Scales for professional caregivers also included work-related factors like coworker conflicts and administrative workload.ConclusionsThere is a critical gap in validated scales to measure agitation-related burden in professional dementia caregivers. Specialized tools are urgently needed to assess this burden and guide support strategies.},
}

@article {pmid41837609,
year = {2026},
author = {Hu, S and Ge, J and Wang, G and Zhao, M and Lv, P and Wang, F and Guo, F and Huang, J and Guan, H and Ma, X and Xing, Z},
title = {Plasma biomarker changes following deep cervical lymphatic venous anastomosis: An exploratory study in Alzheimer's disease using single-molecule array technology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431355},
doi = {10.1177/13872877261431355},
pmid = {41837609},
issn = {1875-8908},
abstract = {BackgroundDeep cervical lymphatic venous anastomosis (dcLVA) is a novel surgical approach for patients with Alzheimer's disease (AD). Its theoretical basis lies in the promotion of the clearance of large biomolecular metabolites in the central nervous system by unblocking the deep cervical lymphatic system. Currently, there is a lack of systematic and comprehensive research on biomarkers for monitoring disease progression and therapeutic efficacy in patients with AD after treatment. Single-molecule technology is applied widely in the field of medicine to detect trace amounts of proteins, especially for detecting the biomarkers related to neurodegenerative diseases such as AD.ObjectiveThis study presents the data of 30 AD patients who underwent dcLVA surgery and the results of analyzing AD biomarkers, exploring the efficacy of dcLVA treatment, and explores whether peripheral blood biomarkers could be used to monitor the treatment effects.MethodsUsing single-molecule technology to detect dynamic changes in blood biomarkers, combined with cognitive scores and Clinician's Interview-Based Impression of Change Plus (CIBIC-plus) data, a prognostic prediction model is constructed.ResultsThe results show that dcLVA surgery elevates peripheral blood amyloid-β (Aβ)42 levels which correlate significantly with the CIBIC plus score. The combination of Aβ42 and Aβ42/40 achieved the highest AUC (0.737) at 180 days post-surgery, showing good diagnostic performance and potential as a prognostic biomarker for dcLVA surgery.ConclusionsBy leveraging the dynamic changes of blood biomarkers, it is helpful to adjust the treatment plan in a timely manner, thereby achieving personalized treatment and improving the treatment effectiveness.},
}

@article {pmid41837631,
year = {2026},
author = {Kim, MG and Woo, SH and Kim, GW and Choi, HK and Kim, KK and Koo, BS},
title = {Efficacy and safety of Woohwangchungsimwon in combination with donepezil for behavioral and psychological symptoms of dementia in probable Alzheimer's disease: An assessor-blinded randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261431692},
doi = {10.1177/13872877261431692},
pmid = {41837631},
issn = {1875-8908},
abstract = {BackgroundWoohwangchungsimwon (WCW) is a traditional Korean herbal formula commonly used to treat anxiety and restlessness. However, its potential role in managing behavioral and psychological symptoms of dementia (BPSD) in Alzheimer's disease (AD) is unclear.ObjectiveThis study evaluated the efficacy and safety of WCW as an adjunctive treatment for BPSD in patients with mild probable AD already receiving donepezil.MethodsSeventy-four patients receiving donepezil 5 mg daily were randomized 1:1 into an intervention group (WCW add-on, n = 37) or a control group (no additional treatment, n = 37) for 24 weeks. The primary outcome was the change in BPSD measured using the Neuropsychiatric Inventory (NPI). Secondary outcomes were cognitive function and emotional and physical well-being, including depression, anxiety, insomnia, quality of life, and severity of dementia. Safety was assessed via adverse events and laboratory results.ResultsSixty-three participants were included. The WCW group demonstrated significantly improved total NPI scores versus controls, particularly in the irritability/lability subdomain. Analysis of covariance (ANCOVA) confirmed these findings in both the full analysis set (FAS) and per-protocol set (PPS). T-test and rank ANCOVA showed significance in the PPS and a trend in the FAS. The general quality of life dementia scale showed a trend toward improvement. No significant differences in adverse events or laboratory results were observed.ConclusionsWCW may be a safe and effective adjunctive therapy for BPSD in patients with mild probable AD. Future studies should adopt more rigorous designs and include patients with broader disease severity to enhance clinical applicability.Trial registrationThe trial was registered with the Clinical Research Information Service (CRIS) on December 10, 2020 (KCT0005669).},
}

@article {pmid41837772,
year = {2026},
author = {Yilmaz, A and Ashrafi, N and Guerra, Z and Goniwiecha, D and Saiyed, N and Gordevičius, J and Krinickis, K and Gabrielaite, M and Osentoski, T and Schumacher, N and Khan, S and Pai, A and Ruff, S and Maddens, ME and Imam, K and Monastero, R and Graham, SF},
title = {Salivary metabolomics for early detection of vascular contributions to cognitive impairment and dementia: Exploring microbiome dysbiosis and sex differences.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423158},
doi = {10.1177/13872877261423158},
pmid = {41837772},
issn = {1875-8908},
abstract = {BackgroundVascular factors contribute to dementia in approximately 20 million individuals, notably in vascular contributions to cognitive impairment and dementia (VCI). However, the lack of specific molecular biomarkers to differentiate VCI from normal aging and Alzheimer's disease (AD) impedes early diagnosis and treatment.ObjectiveTo date the use of saliva for VCI diagnosis has not been previously reported. In this small proof-of-concept study, we aim to explore the feasibility of screening novel salivary diagnostic biomarkers for VCI.MethodsUsing both proton nuclear magnetic resonance ([1]H NMR) spectroscopy and liquid chromatography coupled with mass spectrometry (LC-MS) we biochemically profiled saliva samples collected from individuals with VCI (n = 26) and compared them with cognitively healthy controls (n = 37).ResultsOf the 167 salivary metabolites 56 of them are found to be at significantly different concentrations in the saliva of individuals with VCI as compared to controls. Subsequently, we developed predictive models capable of distinguishing VCI from controls with 0.92 accuracy. Moreover, sex-stratified analysis revealed the perturbation of different metabolic pathways in the saliva of individuals with VCI.ConclusionsThis study underscores the promising role of salivary metabolomics as a non-invasive tool for the early detection of VCI. Our findings suggest that oral microbiome dysbiosis may contribute to VCI pathogenesis, offering novel mechanistic insights. Given the accessibility of saliva, further validation of these robust salivary biomarkers could facilitate scalable, cost-effective screening for VCI, aiding in timely intervention strategies.},
}

@article {pmid41838033,
year = {2026},
author = {Ali, N and Alotaibi, FT and Babu, MA and Singh, TG and Tyagi, Y and Alotaibi, AN and Bansal, N and Puri, S},
title = {Developments on BACE 1 Inhibitors as Anti-Alzheimer Agents: A Perspective on Medicinal Chemistry-Based Advances.},
journal = {Archiv der Pharmazie},
volume = {359},
number = {3},
pages = {e70220},
doi = {10.1002/ardp.70220},
pmid = {41838033},
issn = {1521-4184},
support = {IMSIU-DDRSP2601//Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU)/ ; },
mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism ; Humans ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Structure-Activity Relationship ; Drug Development ; Molecular Structure ; },
abstract = {Alzheimer's disease (AD) is a progressive and complicated neurodegenerative disorder that mostly affects the elderly and is characterized by memory loss, cognitive dysfunction, accumulation of amyloid beta (Aβ) plaques, neurofibrillary tangles, and cholinergic deficits. Current therapies used for AD, such as acetylcholinesterase inhibitors and NMDA receptor antagonist memantine, can only provide temporary or symptomatic relief, but they do not stop or reverse the progression of the disease. Numerous pathogenic hypotheses have been proposed to explain this mechanism; however, the amyloid cascade hypothesis remains the most widely accepted theory, as it suggests that β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) plays a critical role in the generation of Aβ peptides. Therefore, BACE1 may be a key therapeutic target. This review primarily focuses on the key role of BACE1 in AD pathogenesis and describes the development of its inhibitors over three generations, explaining their structure, design, and pharmacological properties. While the first generation lacked brain penetration, the second-generation improved potency but encountered clinical trial failures due to adverse effects. The third generation of these drugs was designed to achieve a balance between efficacy, selectivity, and safety. Additionally, we review the promising molecules currently under clinical investigation, highlighting both their therapeutic potential and the challenges that remain in developing effective disease-modifying therapies for AD treatment.},
}

*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism
Humans
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism
*Alzheimer Disease/drug therapy/metabolism
Animals
Structure-Activity Relationship
Drug Development
Molecular Structure

@article {pmid41830123,
year = {2026},
author = {Aldahish, A and Vasudevan, R and Qasim, SYA and Alshahrani, MS and Almohsen, LK and Alghanoom, SM and AlQahtani, AA and Alshahrani, WK},
title = {Exploring the Epigenetic Mechanisms Underlying Chronic Diseases: A Comprehensive Review.},
journal = {Current gene therapy},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115665232443611260121063601},
pmid = {41830123},
issn = {1875-5631},
abstract = {Epigenetics, the study of heritable changes in gene expression without changes to the DNA sequence, has emerged as an important regulator of disease risk and development. Epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNAs, act as molecular bridges between genetic predisposition and environmental factors. Understanding these changes is critical for determining the pathophysiology of chronic illnesses. This article looks at the involvement of epigenetic mechanisms in chronic diseases such as cardiovascular disease, obesity, depression, Alzheimer's disease, and diabetes mellitus. The emphasis is on recent epigenetic discoveries, their implications for disease risk assessment, and the prospect of epigenetic-based therapeutics in precision medicine. Epigenome-Wide Association Studies (EWAS) and next-generation sequencing technologies have revealed disease-specific epigenetic patterns, underlining their potential as biomarkers for early detection and risk stratification. Epigenetic changes affect important molecular pathways that control metabolic regulation, neuroplasticity, inflammatory response, and cellular homeostasis. Epigenetic modification-targeting therapies, such as DNA methylation inhibitors, histone deacetylase inhibitors, and RNA-based treatments, have shown promise in preclinical and early clinical trials. Epigenetic research offers a transformational framework for understanding the intricate interplay of genetic and environmental variables in chronic illness etiology. Epigenetic alterations are reversible, which opens up new possibilities for therapeutic intervention and individualized therapy. Future research should concentrate on improving epigenetic biomarkers, determining causal links in disease progression, and incorporating epigenetic findings into clinical practice. The advancement of epigenetic medicines has the potential to transform disease prevention, treatment, and global health policies.},
}

@article {pmid41829110,
year = {2026},
author = {Zhang, J and Wu, S and Meng, N and Li, C and Zhao, Y and An, L},
title = {The Mechanism of GABA in Attenuating Neuroinflammation in Alzheimer's Disease: CP/CEBPα/miR-34a-Mediated Suppression of HDAC2/3 in Astrocytes.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/foods15050837},
pmid = {41829110},
issn = {2304-8158},
support = {81903308//National Natural Science Foundation of China/ ; },
abstract = {As a widely available dietary supplement, γ-Aminobutyric acid (GABA) exhibits potential for early intervention against Alzheimer's disease (AD). This study demonstrates that GABA alleviates AD neuroinflammation, and its suppression of astrocytic pro-inflammatory cytokine expression through histone deacetylase (HDAC2/3) inhibition contributes to this effect. Here, in both the cerebral cortex of AD mice and Aβ-exposed U251 cells, pro-inflammatory cytokines and HDAC2/3 expression levels were elevated, whereas the levels of creatine phosphate (CP), CCAAT/enhancer-binding protein α (CEBPα) and microRNA34a (miR-34a) were decreased. GABA treatment counteracted these alterations. Silencing HDAC2 or HDAC3 suppressed pro-inflammatory cytokines. Transfection with miR-34a mimics suppressed pro-inflammatory cytokines and HDAC2/3 expression in U251 cells, while miR-34a inhibitors had the opposite effect. A luciferase reporter assay confirmed HDAC2 as a direct miR-34a target via 3'UTR binding. Knockdown of CEBPα suppressed miR-34a expression, thereby elevating HDAC2/3 and pro-inflammatory cytokine expression in U251 cells. In CP-treated U251 cells, CEBPα and miR-34a expression was elevated, while pro-inflammatory cytokine and HDAC2/3 expression was down-regulated. In conclusion, GABA alleviates neuroinflammation in AD model mice. This effect may be partially attributed to its suppression of astrocyte-derived pro-inflammatory cytokine expression via HDAC2/3 inhibition. The CP/CEBPα/miR-34a pathway mediates the inhibitory effect of GABA on HDAC2/3 expression.},
}

@article {pmid41828536,
year = {2026},
author = {Semyachkina-Glushkovskaya, O and Sursaev, V and Poluektov, M and Diduk, S and Rychkova, L and Madaeva, I and Yakubova, L and Kurths, J},
title = {New Strategies for the Prevention and Therapy of Alzheimer's Disease Based on Stimulation of Brain Drainage and Lymphatic Clearance.},
journal = {International journal of molecular sciences},
volume = {27},
number = {5},
pages = {},
doi = {10.3390/ijms27052312},
pmid = {41828536},
issn = {1422-0067},
support = {23-75-30001//Russian Science Foundation/ ; },
mesh = {*Alzheimer Disease/therapy/prevention & control/metabolism ; Humans ; *Brain/metabolism/pathology ; *Lymphatic Vessels/metabolism ; Amyloid beta-Peptides/metabolism ; COVID-19 ; Low-Level Light Therapy/methods ; Animals ; },
abstract = {Alzheimer's disease (AD) is a serious medical challenge, representing an incurable and insidious disease. Current treatments can slow AD progression but cannot cure it. Promising new methods for AD therapy are essential for addressing the growing number of people with dementia, especially after the COVID-19 pandemic. The review highlights pioneering approaches to AD treatment based on innovative methods for the stimulation of brain drainage and clearance, in which the meningeal lymphatic vessels (MLVs) play a key role. Clinically promising noninvasive technologies using photobiomodulation for the effective clearance of metabolites, including amyloid beta (Aβ), and for the improvement of cognitive impairment during AD progression are discussed. An interesting part of the review is its analysis of innovative methods of improving the efficacy of anti-Aβ immunotherapy by stimulating MLV growth. The review is also focused on lifestyle, including sleep and physical exercises, discussing their support for the efficient lymphatic removal of waste products from the brain. Overall, the review provides an important, informative platform to excite the interest of a wide range of readers in the development of promising and clinically significant strategies for the treatment of AD, based on new strategies for the stimulation of brain drainage and clearance.},
}

*Alzheimer Disease/therapy/prevention & control/metabolism
Humans
*Brain/metabolism/pathology
*Lymphatic Vessels/metabolism
Amyloid beta-Peptides/metabolism
COVID-19
Low-Level Light Therapy/methods
Animals

@article {pmid41828511,
year = {2026},
author = {Zhao, H and Zhang, Z and Wang, C and Lin, F and Cao, H},
title = {Can IVIG Intervene in AD? Insights from Animal Experiments and Clinical Trials-A Systematic Review and Synthesis Without Meta-Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {5},
pages = {},
doi = {10.3390/ijms27052275},
pmid = {41828511},
issn = {1422-0067},
support = {CSBT-SX-2024-04//Shengxiang Blood Transfusion Medicine Development Fund Project of the Chinese Association of Blood Transfusion/ ; Grant No. 2019YFS0105//Science and Technology Project of Sichuan/ ; Grant No. CIFMS, 2021-I2M-1-060//CAMS Innovation Fund for Medical Sciences/ ; },
mesh = {*Immunoglobulins, Intravenous/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism/therapy ; Animals ; Humans ; Clinical Trials as Topic ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; Mice ; },
abstract = {The clinical safety of intravenous immunoglobulin (IVIG) is well-established, offering potential as a "one-drug, multi-target" intervention for Alzheimer's disease (AD). However, its efficacy remains inconclusive and appears closely related to specific functional properties. Therefore, we conducted a systematic review based on the analysis of prior animal and clinical trials to provide insights for future IVIG-based therapeutic development. A systematic search was conducted across PubMed, Embase, the Cochrane Library, Web of Science, PsycInfo, ClinicalTrials.gov, SinoMed, and Wanfang databases for the relevant literature published up to 30 October 2025, using terms related to Alzheimer's, IVIG, and β-amyloid protein. Consequently, IVIG demonstrated clinical safety, though methodologies-including dosages, models, and manufacturers-varied significantly across studies. In most cases, IVIG treatment delayed cognitive degradation in both AD mice and patients. Biologically, Aβ and tau levels increased in plasma while decreasing in the brain or cerebrospinal fluid (CSF), suggesting a peripheral clearance mechanism distinct from that of monoclonal antibody interventions. Additionally, brain atrophy was alleviated, and pathological plaques were reduced. In the context of plasma exchange (PE) combination therapy, the administration of IVIG further contributed to improvements in language, memory, and praxis. IVIG possesses a favorable safety profile and can ameliorate AD symptoms, yet efficacy varies considerably between trials. To advance treatment, future research should investigate the reasons for these variances and establish a standardized system for evaluating preclinical IVIG interventions, thereby facilitating the development of specific IVIG products for AD.},
}

*Immunoglobulins, Intravenous/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism/therapy
Animals
Humans
Clinical Trials as Topic
Amyloid beta-Peptides/metabolism
Disease Models, Animal
Mice

@article {pmid41827870,
year = {2026},
author = {Amrutha, S and Prasad, TSK and Modi, PK},
title = {Glycyrrhizic Acid Attenuates Aβ42-Induced Neurodegeneration Through Coordinated Regulation of Oxidative Stress, Synaptic Markers, and Key Alzheimer's Signaling Pathways.},
journal = {Cells},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/cells15050436},
pmid = {41827870},
issn = {2073-4409},
support = {YU/Seed grant/134-2022//Yenepoya (Deemed to be University)/ ; },
mesh = {*Glycyrrhizic Acid/pharmacology/therapeutic use ; *Amyloid beta-Peptides/toxicity/metabolism ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Oxidative Stress/drug effects ; Humans ; *Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; *Peptide Fragments/toxicity ; *Synapses/metabolism/drug effects ; Apoptosis/drug effects ; Neurons/drug effects/metabolism/pathology ; Neuroprotective Agents/pharmacology ; Biomarkers/metabolism ; Cell Line ; },
abstract = {Alzheimer's disease (AD) is a catastrophic neurodegenerative disorder marked by progressive decline of cognitive function, memory loss, and neuronal death. Its pathology is characterized by the formation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles from tau hyperphosphorylation. Despite extensive research, current treatments are limited to symptomatic relief and are associated with significant side effects. This accentuates the critical need for alternative therapeutic strategies with potent neuroprotective effects and minimal toxicity. This study investigates the neuroprotective potential of glycyrrhizic acid, as the precise molecular mechanisms by which it might improve AD pathology remain poorly understood. Using an Aβ42-induced IMR-32 cell model of AD, our research revealed that Aβ42 treatment caused significant protein alterations associated with AD pathology, mitochondrial dysfunction, cell cycle re-entry, and synaptic activity. Co-treatment with glycyrrhizic acid not only restored these protein levels, but also mitigated the hyperactivation of several key signaling pathways and rescued neurons from apoptosis. These findings suggest that glycyrrhizic acid exerts neuroprotective effects by preventing mitochondrial dysfunction and apoptosis via modulation of critical signaling pathways. This study provides strong evidence for glycyrrhizic acid's neuroprotective properties in AD, paving the way for further research into its potential as a promising therapeutic agent for Alzheimer's disease.},
}

*Glycyrrhizic Acid/pharmacology/therapeutic use
*Amyloid beta-Peptides/toxicity/metabolism
*Alzheimer Disease/metabolism/drug therapy/pathology
*Oxidative Stress/drug effects
Humans
*Signal Transduction/drug effects
Mitochondria/drug effects/metabolism
*Peptide Fragments/toxicity
*Synapses/metabolism/drug effects
Apoptosis/drug effects
Neurons/drug effects/metabolism/pathology
Neuroprotective Agents/pharmacology
Biomarkers/metabolism
Cell Line

@article {pmid41827316,
year = {2026},
author = {Hasanein, D and Lighezan, DF and Țunea, OE and Ciobotaru, VG and Bașa, NS},
title = {Atrial Fibrillation and Cognitive Decline: Mechanisms, Evidence, and Preventive Strategies-A Narrative Review.},
journal = {Journal of clinical medicine},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/jcm15051899},
pmid = {41827316},
issn = {2077-0383},
support = {Not applicable//Victor Babeș University of Medicine and Pharmacy Timișoara/ ; },
abstract = {Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is increasingly recognized as a risk factor for cognitive decline and dementia, independent of clinically apparent stroke. This narrative review synthesizes current evidence on pathophysiological mechanisms linking AF to cognitive decline, including cerebral hypoperfusion, silent cerebral infarction, microembolism, systemic inflammation, and shared vascular risk factors. A structured literature search was conducted in PubMed and ScienceDirect from January 2000 to October 2025, with evidence quality assessed using adapted Newcastle-Ottawa Scale criteria. Observational evidence suggests that oral anticoagulation, particularly with direct oral anticoagulants (DOACs), may be associated with reduced dementia risk compared to no treatment or vitamin K antagonists. However, most intervention studies were not designed with cognitive endpoints as primary outcomes, limiting causal inference. Current evidence supports comprehensive AF management, including guideline-directed anticoagulation, appropriate rhythm or rate control, and aggressive modification of shared risk factors. Atrial fibrillation is consistently associated with increased risk of cognitive decline and dementia through multiple interrelated mechanisms; however, randomized trials with cognitive endpoints are needed to establish causality.},
}

@article {pmid41825656,
year = {2026},
author = {Dong, M and Guo, ZG and Zhang, Y and Luo, J and Zhang, J},
title = {Optimal control of Alzheimer's disease model via multi-target combination therapy.},
journal = {Journal of theoretical biology},
volume = {},
number = {},
pages = {112425},
doi = {10.1016/j.jtbi.2026.112425},
pmid = {41825656},
issn = {1095-8541},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of toxic protein plaques in the brain. Abundant evidence indicates that β-amyloid (Aβ) serves as an important pathological hallmark in AD, with Aβ oligomers (Aβo) exhibiting critical neurotoxicity. The imbalance of Ca[2+] homeostasis has also been demonstrated to exhibit complex interplay with abnormal Aβ accumulation. Several Aβ-targeting drugs are currently employed in the treatment of AD. However, the multifactorial mechanisms driving AD contribute to the suboptimal efficacy of existing clinical therapies. Motivated by these factors, multi-target combination therapies emerge as the prominent trend in AD research. In this paper, we propose an optimal control model to describe Aβo dynamics under multi-target combined therapy. Also, the basic reproduction number R0 is derived as a threshold parameter to characterize the AD process. We find that Aβo can be maintained at a low steady state when R0 < 1, indicating the potential for disease control. The results of parameter sensitivity analysis based on R0 further confirm the significant impact of control variables on the system evolution. Subsequently, we investigate the theoretical results of the optimality system, proving the existence and uniqueness of the optimal solution. Numerical simulations are conducted to demonstrate the control efficacy of different strategies, revealing that drug combination therapy exhibits superior control over Aβo steady-state compared to mono therapy. Moreover, cost-effectiveness analysis is employed to compare different control strategies, with the objective of identifying the optimal approach that balances drug costs with therapeutic efficacy. Notably, appropriately lowering the drug dosage in triple therapy retains the potential for maintaining therapeutic effects, thereby improving drug cost control. In summary, this work provides important insights into multi-target combination therapy for early treatment of AD.},
}

@article {pmid41825614,
year = {2026},
author = {Yang, H and Zhou, H and Zhao, K and Shi, L and Li, Y and Zhao, Q and Ya, J and Wu, C},
title = {PDGF-BB mitigates pericyte injury by activating the PHF19-PRC2 complex via the miR-221/BRCA1 signaling axis in Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111819},
doi = {10.1016/j.brainresbull.2026.111819},
pmid = {41825614},
issn = {1873-2747},
abstract = {BACKGROUND: Platelet-derived growth factor-BB (PDGF-BB) is a critical factor in maintaining pericyte function. Damage to pericytes has been shown to accelerate the progression of Alzheimer's disease (AD). This study aimed to investigate the role of PDGF-BB in the pathogenesis of AD.

METHODS: Pericytes were treated with Aβ1-42 alone or in combination with PDGF-BB. Cell viability, proliferation, and apoptosis were assessed using the CCK-8 assay, EdU assay, and flow cytometry, respectively. Co-immunoprecipitation was performed to investigate the interactions among BRCA1, PHF19, EZH2, EED, SUZ12, and RbAp46/48. The relationships among BRCA1, miR-221-3p, and miR-222-3p were evaluated using a luciferase reporter assay. APP/PS1 transgenic mice were administered PDGF-BB, and behavioral performance was assessed via the Morris water maze test. Immunofluorescence staining and Evans Blue assay were employed to examine pericyte coverage and blood-brain barrier (BBB) integrity.

RESULTS: PDGF-BB enhanced cell viability and proliferation while inhibiting apoptosis in Aβ1-42-treated pericytes; these effects were reversed by BRCA1 overexpression. BRCA1 expression was upregulated in pericytes exposed to Aβ1-42. Furthermore, PDGF-BB treatment resulted in the downregulation of BRCA1 and the upregulation of members of the PHF19-PRC2 complex, including PHF19, EZH2, EED, SUZ12, and RbAp46/48. BRCA1 was found to interact with these PHF19-PRC2 complex components. Additionally, miR-221 suppressed BRCA1 expression by directly targeting BRCA1, whereas miR-222 interacted with BRCA1 without affecting its expression. In vivo, PDGF-BB administration improved learning and memory abilities, increased pericyte coverage, and enhanced blood-brain barrier integrity in an Alzheimer's disease mouse model.

CONCLUSION: PDGF-BB activated PHF19-PRC2 complex through the regulation of the miR-221/BRCA1 axis, thereby decreasing blood-brain barrier permeability and improving learning and memory abilities in AD mouse models. Consequently, PDGF-BB may have a therapeutic potential in the progression of AD.},
}

@article {pmid41825555,
year = {2026},
author = {Li, W and Chen, S and Liu, Z and Lei, B and Lin, X and Ying, J and Lin, Z and Chen, L and Rowan, MJ and Hu, N and Wang, Q and Li, L},
title = {Differential effects and underlying mechanisms of voluntary, forced, and combined exercise on ameliorating Alzheimer's disease pathophenotypes.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115731},
doi = {10.1016/j.expneurol.2026.115731},
pmid = {41825555},
issn = {1090-2430},
abstract = {BACKGROUND: Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disorder characterized by extracellular Aβ accumulation and intracellular tau hyperphosphorylation. Currently, there are no effective therapeutic drugs available for AD. Regular exercise training has emerged as a promising physical intervention strategy for mitigating both the risk and progression of AD, but different types of exercise interventions show varied and conflicting results in AD treatment, with their differential effects and mechanisms still unelucidated.

METHODS: Using an Aβ oligomer-induced AD mouse model, we investigated therapeutic effects of voluntary wheel running, forced treadmill running, and combined exercise (voluntary combined with forced running) on AD pathologies. For depressive-like behavior, we conducted forced swimming test and tail suspension test; for cognition, Novel object recognition test (object recognition ability) and Morris water maze test (spatial learning and memory) was used respectively. We applied BrdU-DCX/NeuN/GFAP immunofluorescence co-staining to measure neurogenesis, Western blot to examine proteins associated with synapses, neurons, astrocytes, apoptosis, and BDNF signaling key components, serum metabolomics to identify exercise-induced metabolites. Furthermore, a clinical trial involving healthy subjects and patients with AD implemented an acute exercise intervention and utilized portable functional near-infrared spectroscopy to assess cortical activation and functional connectivity under conditions of both voluntary and forced exercise.

RESULTS: Voluntary, forced, and combined exercise alleviated depressive-like phenotypes and short-term cognitive deficits in AD mice, while only forced exercise conferred sustained long-term memory benefit. All exercises boosted hippocampal neurogenesis by enhancing newborn cell (BrdU[+] cells) proliferation, promoting differentiation into immature neurons (BrdU[+]DCX[+] cells), and maintaining newborn astrocytes (BrdU[+]GFAP[+] cells). Forced/combined exercise sustained immature neurons (DCX[+] cells), and forced exercise alone significantly elevated mature newborn neurons (BrdU[+]NeuN[+] cells). Neuroprotective mechanisms may involve the modality-specific BDNF-TrkB signaling and BAX-dependent apoptosis regulation. Exercise-induced metabolites (amino acid homeostasis, energy provision, oxidative defense) strongly correlated with neurogenesis and neural function. In AD patients, acute voluntary exercise was associated with enhanced left prefrontal cortex activity, whereas acute forced exercise increased bilateral motor cortex activation.

CONCLUSIONS: Our findings reveal distinct neuroprotective profiles of long-term voluntary, forced, and combined exercise interventions against Aβ oligomer neurotoxicity in an AD mouse model, and different acute exercise modalities also demonstrate distinct effects on cortical activation and functional connectivity in patients with AD. Our study provides novel insights into exercise modalities' therapeutic effects in ameliorating AD neuropathology.},
}

@article {pmid41825224,
year = {2026},
author = {Soria-Tobar, L and Ouro-Corredera, D and Roman-Valero, L and Hernández, F and Millán, JL and Álvarez-Castelao, B and Sebastián-Serrano, Á and Aivar, P and Díaz-Hernández, M},
title = {Neuronal alkaline phosphatase promotes the spread of Tau-induced pathology, and its blockade prevents neurodegeneration and memory loss.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {2},
pages = {e00869},
doi = {10.1016/j.neurot.2026.e00869},
pmid = {41825224},
issn = {1878-7479},
abstract = {Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders marked by abnormal intraneuronal aggregates of phosphorylated Tau protein. Unfortunately, no effective treatment is currently available. Since extracellular Tau (eTau) is essential for the spread of cerebral tauopathy, immunotherapy approaches using specific antibodies against Tau have been investigated. However, these strategies have shown limited applicability and benefit. Because previous in vitro studies reported that dephosphorylation of eTau by tissue-nonspecific alkaline phosphatase (TNAP) enhances its neurotoxicity, here we evaluate how neuronal TNAP contributes to Tau-induced neurotoxicity in vivo. To address this, we generated new transgenic mouse lines using Cre-lox technology to i) specifically delete TNAP in excitatory neurons of P301S mice, a well-characterized tauopathy model, or ii) induce neuronal TNAP overexpression in WT mice. Moreover, we compare the in vivo spreading capacity of phospho-eTau and dephospho-eTau-induced neurotoxicity. Our findings show that neuronal TNAP deletion in P301S mice reduces i) neuronal and synaptic loss, ii) the number of neurons with neurofibrillary tangles (NFTs), iii) reactive astrogliosis and microgliosis, and iv) brain calcifications; collectively, these changes lead to v) improved memory function in these mice. Conversely, overexpression of neuronal TNAP in WT mice alone is sufficient to cause i) loss of thalamic neurons and synaptic contacts, ii) formation of intracellular NFTs, iii) reactive gliosis, iv) brain calcifications, and v) memory impairment. These results demonstrate that neuronal TNAP promotes Tau-induced neurotoxicity spreading by facilitating eTau dephosphorylation, which confirms this ectoenzyme as a promising therapeutic target for tauopathies.},
}

@article {pmid41825212,
year = {2026},
author = {da Silva, AMP and Januário Campos Cardoso, L and Batista, S and Gonçalves, OR and Paranhos, T and Teixeira, IPS and Guimarães, PD and Espinosa Franco, B and Cal, H and Salles, JEN and Perry, G and Høilund-Carlsen, PF and Santos, DH},
title = {Tirzepatide versus semaglutide for the prevention of mild cognitive impairment, dementia, and Alzheimer's disease in type 2 diabetes: A real-world, retrospective cohort study.},
journal = {Journal of diabetes and its complications},
volume = {40},
number = {5},
pages = {109306},
doi = {10.1016/j.jdiacomp.2026.109306},
pmid = {41825212},
issn = {1873-460X},
abstract = {BACKGROUND: Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in managing type 2 diabetes mellitus (T2DM) and provide metabolic and cardiovascular benefits. Their associations with neurocognitive outcomes in clinical populations remain uncertain.

METHODS: We conducted a retrospective, population-based cohort study using de-identified electronic health records from the global TriNetX research network, predominantly comprising U.S.-based healthcare organizations. Adults with T2DM who initiated tirzepatide or semaglutide were included. Propensity score matching (1:1) was applied to balance baseline characteristics, including age, sex, race, and cardiometabolic and psychiatric comorbidities. Incident diagnoses of mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD) occurring at least 12 months after treatment initiation were assessed using risk ratios (RRs) and time-to-event analyses with Kaplan-Meier estimators.

FINDINGS: A total of 290,606 patients initiated semaglutide and 44,471 initiated tirzepatide. After propensity score matching, each group included 44,470 patients. Compared with semaglutide, initiation of tirzepatide was associated with a lower risk of MCI (RR 0.12; 95% CI 0.06-0.22), dementia (RR 0.15; 95% CI 0.09-0.26), and AD (RR 0.48; 95% CI 0.22-1.01). Absolute risks were low for all outcomes, and separation of survival curves was more consistent for MCI than for dementia or AD.

INTERPRETATION: In this real-world observational analysis of adults with T2DM, initiation of tirzepatide was associated with a lower incidence of MCI compared with semaglutide, whereas associations for dementia and AD were less consistent. These findings should be interpreted descriptively and as hypothesis-generating. Prospective randomized trials with longer follow-up and systematic neurocognitive assessment are needed to clarify whether, and under which conditions, incretin-based therapies influence neurocognitive outcomes.},
}

@article {pmid41824917,
year = {2026},
author = {Fallica, AN and Barbaraci, C and Ruiz-Cantero, MC and Scarlatti, A and Coco, A and Giordano, G and La Mantia, A and Prezzavento, O and Di Stefano, A and Cacciatore, I and Siano, G and Cattaneo, A and Pasquinucci, L and Cobos, EJ and Di Primio, C and Amata, E and Marrazzo, A},
title = {Modulation of Tau Protein Neurotoxic Hallmarks by Novel σ1R Agonists/HDAC Inhibitor Dual-Acting Compounds.},
journal = {ChemMedChem},
volume = {21},
number = {5},
pages = {e202500922},
doi = {10.1002/cmdc.202500922},
pmid = {41824917},
issn = {1860-7187},
support = {P20224L3NK//Ministero dell'Università e della Ricerca/ ; 2022Z3BBPE//Ministero dell'Università e della Ricerca/ ; 2022HRS4YB//Ministero dell'Università e della Ricerca/ ; },
mesh = {*Receptors, sigma/agonists/metabolism ; *Histone Deacetylase Inhibitors/pharmacology/chemistry/chemical synthesis ; *tau Proteins/metabolism/antagonists & inhibitors ; Sigma-1 Receptor ; Humans ; Animals ; Structure-Activity Relationship ; Mice ; Molecular Structure ; Dose-Response Relationship, Drug ; Histone Deacetylases/metabolism ; },
abstract = {Neurodegenerative diseases, like Alzheimer's disease (AD), are characterized by the accumulation of tau aggregates, leading to neuronal dysfunction and cognitive decline. This study explores the development of dual-acting compounds combining sigma-1 receptor (σ1R) agonists and histone deacetylase inhibitors (HDACi) to target these pathological mechanisms. Compounds 2d and 3a demonstrated high affinity for σ1R and significantly reduced tau aggregation and phosphorylation in vitro, notably at the AT8 epitope. These dual-acting compounds destabilized tau aggregates, increased tau solubility, and showed favorable pharmacokinetic properties, with compound 2d exhibiting enhanced chemical stability and longer half-life than 3a. In vivo, both compounds confirmed a σ1R agonist profile by reversing the effect of the σ1R antagonist BD-1063. This dual-action approach, acting on both HDAC and σ1R pathways, holds significant potential for treating tauopathies. While further optimization and clinical evaluation are needed, these findings provide a strong foundation for the continued development of multimodal therapies for neurodegenerative diseases treatment.},
}

*Receptors, sigma/agonists/metabolism
*Histone Deacetylase Inhibitors/pharmacology/chemistry/chemical synthesis
*tau Proteins/metabolism/antagonists & inhibitors
Sigma-1 Receptor
Humans
Animals
Structure-Activity Relationship
Mice
Molecular Structure
Dose-Response Relationship, Drug
Histone Deacetylases/metabolism

@article {pmid41824288,
year = {2026},
author = {Saad, HM and Atef, E and Aboushouk, AA and Waheeb, TS and Elsayed, AE and Mohammed, SAA},
title = {Cross-talk between pyroptosis and miRNAs in Alzheimer disease neuropathology, therapeutic targeting of NLRP inflammasomes, and recent advances in nanoparticle-targeted therapy.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlag014},
pmid = {41824288},
issn = {1554-6578},
abstract = {Alzheimer disease (AD) is a widespread neurodegenerative disorder. It is pathologically marked by the deposition of β-amyloid (Aβ) plaques and a high phosphorylation level of tau proteins, resulting in neurofibrillary tangle development, cognitive decline, and neuronal loss. Previous studies showed the correlation between AD and pyroptosis, an inflammasome-mediated programmed cell death. It was reported that Aβ and tau deposits may activate the NOD-like receptor pyrin domain-3 (NLRP3) and inflammasome-caspase-1-gasdermin D (GSDMD) pathway. This leads to cell membrane rupture and discharge of IL-1β and IL-18 cytokines that initiate neuroinflammation. However, there is still a lack of research on therapeutic approaches that target the pyroptotic pathway in AD. This review documents recent research on the regulatory function of miRNAs in regulating the NLRP3/caspase-1/GSDMD pathways and their potential to lessen pyroptosis-induced neuronal damage. We also address novel platforms for delivering antipyroptotic drugs and miRNA modulators across the blood-brain barrier using nanotechnology, such as engineered nanocarriers and exosome-like nanoparticles. These approaches have a promising therapeutic implication as potential treatment options for AD by combining molecular regulation and nanomedicine.},
}

@article {pmid41823963,
year = {2026},
author = {Fu, W and Qian, Y and Karimi, SM and Zarei, H and Chen, X},
title = {Risk Adjustment for Alzheimer Disease and Related Dementias in Medicare Advantage and Health Care Experiences.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e261796},
doi = {10.1001/jamanetworkopen.2026.1796},
pmid = {41823963},
issn = {2574-3805},
mesh = {Humans ; United States ; *Medicare Part C/statistics & numerical data/economics ; Male ; Female ; Cross-Sectional Studies ; *Risk Adjustment/methods/statistics & numerical data ; Aged ; *Alzheimer Disease/economics/therapy/epidemiology ; Aged, 80 and over ; *Dementia/economics/therapy ; Quality of Health Care ; Health Services Accessibility/statistics & numerical data ; },
abstract = {IMPORTANCE: Failure to account for the full complexity and costs of high-need populations in the risk-adjusted capitated payment model for Medicare Advantage (MA) plans may create financial disincentives for plans to invest in comprehensive care for affected beneficiaries, potentially exacerbating health disparities.

OBJECTIVE: To evaluate the association of reinstatement of Alzheimer disease and related dementias (ADRD) hierarchical condition categories (HCCs) into the MA risk-adjusted payment model in 2020 with access, affordability, and quality of care for beneficiaries with ADRD.

This cross-sectional study examined a nationally representative sample of MA beneficiaries from the Medicare Current Beneficiary Survey (2015-2022). Beneficiaries with ADRD and those without ADRD but with comparable neurological diseases (stroke, paralysis, or Parkinson disease) before and after 2020 were included. Data analyses were performed between January and December 2025.

EXPOSURES: Reinstatement of the ADRD HCC into the MA risk adjustment formula in 2020.

MAIN OUTCOMES AND MEASURES: Primary outcomes were accessibility of needed care, medical financial burden, satisfaction with specialist access, and satisfaction with quality of care. These outcomes were assessed using a difference-in-differences model to compare changes between the treatment and control group before and after the inclusion of ADRD HCCs in the MA risk adjustment model in 2020.

RESULTS: Among 5353 MA beneficiary observations (1239 [23.1%] aged 65-74 years; 3127 [58.4%] aged ≥75 years; 1785 male [33.3%]), 1629 (30.4%) reported a diagnosis of ADRD, and 3724 (69.6%) did not report an ADRD diagnosis. Compared with MA beneficiaries without ADRD, those with ADRD reported lower rates of difficulty accessing care (142 beneficiaries [8.7%] vs 394 beneficiaries [10.6%]) and medical financial burden (235 beneficiaries [19.3%] vs 740 beneficiaries [25.1%]), but slightly lower rates of satisfaction with specialist access (1384 beneficiaries [90.8%] vs 3267 [92.7%]) and care quality (1495 beneficiaries [92.8%] vs 3414 beneficiaries [93.0%]). Reintroducing ADRD HCCs into the MA risk-adjusted payment model was associated with a 6.62 percentage-point decrease in reporting any troubles accessing needed care (β = 0.06; 95% CI, -0.11 to -0.02; P = .005) and a 9.20 percentage-point decrease in reporting any medical financial burden (β = -0.09; 95% CI, -0.16 to -0.02; P = .009) among MA beneficiaries with ADRD. No significant association was observed for satisfaction with specialist access or with quality of care among MA beneficiaries with ADRD.

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of MA beneficiaries, reintroducing ADRD HCCs into the MA risk adjustment model was associated with improved care access and reduced financial burden among MA beneficiaries with ADRD. These findings suggest that risk adjustment that better reflects the costs of chronic, complex conditions may better align MA plan incentives with the needs of high-need populations and promote care equity.},
}

Humans
United States
*Medicare Part C/statistics & numerical data/economics
Male
Female
Cross-Sectional Studies
*Risk Adjustment/methods/statistics & numerical data
Aged
*Alzheimer Disease/economics/therapy/epidemiology
Aged, 80 and over
*Dementia/economics/therapy
Quality of Health Care
Health Services Accessibility/statistics & numerical data

@article {pmid41823692,
year = {2026},
author = {Fryk, E and Rodrigues Silva, VR and Strindberg, L and Gisslén, M and Zetterberg, H and Blennow, K and Jansson, PA},
title = {Effect of 6-week tadalafil treatment on blood-based biomarkers of neurodegeneration: A post-hoc analysis of a randomized controlled trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261421227},
doi = {10.1177/13872877261421227},
pmid = {41823692},
issn = {1875-8908},
abstract = {Phosphodiesterase-5 (PDE-5) inhibitors may be beneficial in Alzheimer's disease (AD). We assessed the PDE-5 inhibitor tadalafil effect on plasma biomarkers of neurodegeneration in 15 individuals with type 2 diabetes post-hoc in a randomized placebo-controlled trial (ClinicalTrials.gov: NCT02601989) at Sahlgrenska University Hospital. Tadalafil reduced plasma amyloid-β 40 and 42 but not the 42/40 ratio over a 6-week treatment period. Glial fibrillary acidic protein was reduced, but not phosphorylated tau217, neurofilament light protein or growth/differentiation factor 15. Tadalafil reduced plasma levels of biomarkers for amyloid metabolism and astroglial activation in patients with diabetes. Designated clinical trials are warranted to validate these results.},
}

@article {pmid41823666,
year = {2026},
author = {Faucher, C and Thienel, R and Behler, A and Gomez, L and Fripp, J and Breakspear, M and Lupton, MK},
title = {The relationship between napping and memory varies as a function of genetic risk for Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427707},
doi = {10.1177/13872877261427707},
pmid = {41823666},
issn = {1875-8908},
abstract = {BackgroundHabitual daytime napping is a significant aspect of many older adults' sleep-wake cycle. Growing evidence links napping and cognition in the context of Alzheimer's disease (AD), yet little is known about how genetic risk influences this relationship.ObjectiveThis study investigates interactions between genetic risk for AD and napping on cognition in 1655 cognitively healthy middle-aged to older adults.MethodsCognition was assessed using a self-administered online battery and reduced to three variables: memory, visuospatial abilities and executive functions. Genetic risk was assessed with the presence of APOE ɛ4 allele and polygenic risk scores for AD (PRS; excluding APOE). ANCOVA assessed interactions.ResultsThere was a significant interaction between APOE ɛ4 and napping duration on the memory component (F(2,1645) = 3.84, p = 0.022, ηp[2] = 0.005). APOE ɛ4 carriers reporting long naps demonstrated better memory than non-carriers also reporting long naps. Among APOE ɛ4 carriers, those who napped for ≥ 1 h performed better than those reporting shorter naps. In a separate analysis, there was a significant interaction between PRS and napping (F(2653) = 3.44, p = 0.033, ηp[2] = 0.010). Low PRS was related to better memory than high PRS among those who did not nap. Within the low PRS group, participants who did not nap outperformed those reporting short naps. Results remained significant after accounting for overnight sleep efficiency.ConclusionsFindings suggest that the relationship between napping and memory may vary as a function of genetic risk for AD. Results could inform studies looking into personalized preventative treatment based on genetic profiles.},
}

@article {pmid41823662,
year = {2026},
author = {Cho, JI and Kim, K},
title = {Polluted air and fading memory: Effects of air pollution on Alzheimer's disease and vascular dementia.},
journal = {Journal of the Air & Waste Management Association (1995)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/10962247.2026.2639371},
pmid = {41823662},
issn = {2162-2906},
abstract = {Air pollution is widely recognized as a major public health concern, and emerging evidence suggests an association with dementia. Establishing a causal relationship, however, is difficult. Economic cycles affect both dementia prevalence and pollution levels: during economic booms, financial resources for treatment rise, but so do air pollution and work-related stress. In South Korea, air quality has generally improved, even as Alzheimer's cases have increased with population aging, indicating a time-series relationship that biases regression results. Air pollution and vascular dementia also temporarily declined during COVID-19, reflecting omitted variable bias. To address these endogeneity concerns, we use wind speed and direction as instruments for air pollution in South Korea. Our estimates show that higher concentrations of PM10, PM2.5, and NO2 significantly increase dementia cases, with instrumental variable results substantially larger than ordinary least squares, underscoring the importance of correcting for bias. These findings carry important policy implications. Because air pollution is a negative externality, its health consequences-including dementia-extend beyond individual responsibility and represent broader social costs. Reducing pollution could therefore not only improve health outcomes but also ease the considerable economic burden of dementia care. As air pollution disproportionately affects vulnerable groups-individuals with dementia who are unable to sustain employment or income-targeted social support is also essential to address their combined medical and financial challenges.Implications: We underscore the importance of addressing endogeneity issues when evaluating the relationship between air pollution and dementia. Conventional approaches may produce biased estimates due to spurious time-series-correlations and omitted variables. By using wind speed and direction as instruments, we identify LATE-based causal effects of air pollution on the number of dementia patients. Our findings suggest important policy implications: reducing air pollution can lower the substantial social and economic costs associated with dementia. Improved administrative data linking clinical records with environmental exposures would support effective monitoring and policy evaluation. Furthermore, international cooperation is needed to address transboundary nature of air pollution.},
}

@article {pmid41823189,
year = {2026},
author = {Liao, W and Yu, Q and Chen, B and Chen, H and Zou, L and Xie, H and Chen, H and Wang, C and Li, Y and Gao, X and Guo, H and Yang, Y and She, Z and Zeng, Q and Zhang, Z and Li, G and Feng, S and Lin, H and Ouyang, J and Liang, J and Ao, W and Zeng, Q and Liu, Z and Weng, H and Huang, H and Zhu, F and Liu, R and Wang, Y and Yu, D and Li, X and Mai, Y and Jiang, S and Tu, Y and Li, Z and Liu, J and , },
title = {Effectiveness, safety, and biomarker dynamics of lecanemab in Chinese Alzheimer's disease population: a multicenter real-world study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71231},
doi = {10.1002/alz.71231},
pmid = {41823189},
issn = {1552-5279},
support = {82171178//National Natural Science Foundation of China/ ; 82371186//National Natural Science Foundation of China/ ; 2025A031003//Guangzhou Municipal Health Science and Technology Project/ ; BSAA2024-AD-01004//Guangdong Association for Brain Science Application/ ; 20231800936092//Dongguan Science and Technology of Social Development Program/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; /AG/NIA NIH HHS/United States ; U19AG024904//National Institutes of Health Grant/ ; //Northern California Institute for Research and Education/ ; /EB/NIBIB NIH HHS/United States ; /CAPMC/CIHR/Canada ; //National Institutes of Health (FNIH)/ ; //Alzheimer's Association; Alzheimer's Drug/ ; //Discovery Foundation/ ; //Araclon Biotech; BioClinica, Inc./ ; //Biogen; BristolMyers Squibb Company/ ; //CereSpir, Inc./ ; //Cogstate; Eisai Inc./ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //Genentech, Inc./ ; //Fujirebio; GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Lumosity; Lundbeck; Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company; and Transition Therapeutics/ ; //2025 Brain Health Youth Fund - Precision Diagnosis and Treatment Research for Alzheimer's Disease/ ; 2024A04J3549//Technologies R&D Program of Guangzhou/ ; //Key Medical Discipline of Guangzhou (2025-2027)/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Male ; Female ; Biomarkers/blood ; Aged ; Positron-Emission Tomography ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Prospective Studies ; China ; *Cognitive Dysfunction/drug therapy ; Aged, 80 and over ; Neuropsychological Tests ; East Asian People ; },
abstract = {BACKGROUND: Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown.

METHODS: In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months.

RESULTS: Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences.

CONCLUSION: Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging
Male
Female
Biomarkers/blood
Aged
Positron-Emission Tomography
Amyloid beta-Peptides/blood
tau Proteins/blood
Prospective Studies
China
*Cognitive Dysfunction/drug therapy
Aged, 80 and over
Neuropsychological Tests
East Asian People

@article {pmid41823023,
year = {2026},
author = {Yirün, A and Çakır, DA and Erdemli Köse, SB and Özyurt, AB and Demirel, G and Erkekoglu, P},
title = {Determination of the effects of Herpes simplex glycoprotein B on epigenetic alterations in in vitro models of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261427784},
doi = {10.1177/13872877261427784},
pmid = {41823023},
issn = {1875-8908},
abstract = {BackgroundEpigenetic dysregulation is increasingly recognized as a key mechanism in the development and progression of Alzheimer's disease (AD). Herpes simplex virus type 1 (HSV-1) infection has been proposed as a potential biological trigger that may accelerate neurodegeneration through epigenetic modifications. Among HSV-1 structural proteins, glycoprotein B (HSV-gB) may influence host-virus interactions affecting neuronal gene regulation.ObjectiveThis study aimed to investigate the contribution of HSV-gB to AD-related epigenetic alterations and to determine whether HSV-gB exposure exacerbates epigenetic dysregulation in two in vitro neuronal AD models.MethodsHuman SH-SY5Y neuroblastoma cells were used to establish two AD models: a differentiation-based aging model induced by retinoic acid and brain-derived neurotrophic factor (RA + BDNF), and an amyloid aggregation model induced by amyloid-β 1-42 (Aβ1-42). Cells were treated with HSV-gB (190.5 pg/ml) alone or in combination with each model. Global DNA methylation, histone H3 and H4 acetylation, histone multiplex modifications, and HDAC3 and HDAC8 levels were analyzed using ELISA-based assays.ResultsHSV-gB exposure and RA + BDNF treatment induced global DNA hypomethylation and histone hypoacetylation, accompanied by significant increases in HDAC3 and HDAC8 levels. In contrast, the Aβ1-42 model showed DNA hypermethylation and histone hyperacetylation, indicating distinct epigenetic profiles between differentiation-associated aging and amyloid-driven pathology.ConclusionsHSV-gB contributes to AD-related epigenetic dysregulation and may amplify neurodegenerative mechanisms through HDAC-mediated chromatin remodeling. The findings highlight divergent epigenetic signatures in different AD models and support a potential role for viral factors in modulating AD-associated epigenetic pathways.},
}

@article {pmid41822848,
year = {2026},
author = {Bachevalier, J and Weiss, AR},
title = {Role of the Primate Perirhinal Cortex in Memory and Emotional Regulation: Ontogeny and Early Insults.},
journal = {Medical research archives},
volume = {14},
number = {2},
pages = {},
pmid = {41822848},
issn = {2375-1916},
abstract = {The perirhinal cortex, a small strip of the anterior medial temporal cortex, first came into prominence through studies of memory. While examining patients with damage to the medial temporal lobe as well as animals with similar regional damage, findings showed that combined damage to the hippocampus, amygdala, and adjacent cortical areas, including the perirhinal cortex, were responsible for the profound memory loss observed. Later, however, the evidence demonstrated that the accompanying damage to the underlying medial temporal cortical areas were largely responsible for the memory deficit that had been attributed to the combined hippocampal and amygdala lesions. The perirhinal cortex has become appreciated as a critical structure supporting familiarity judgement, recognition memory, flexible executive control and behavioral regulation. The objective of this article is first to review the anatomy of the perirhinal cortex and its interactions with other medial temporal structures as well as the neocortex. A series of neurosurgical ablation studies in nonhuman primates will provide evidence for its role in memory and behavioral regulation in adulthood. The next section will highlight the functional maturation of the perirhinal from infancy through adulthood and will show that its role in support of recognition memory emerges in early infancy. The findings will also show that the neonatal perirhinal dysfunction results in functional compensation of recognition and working memory in adulthood but impacts higher-order executive processes such as cognitive control and flexibility. Interestingly, the discovery of the role of perirhinal cortex in familiarity judgements instead of recollection, which is mediated by the hippocampus, is now well documented in several clinical neurodevelopmental disorders (epilepsy, Alzheimer's disease, schizophrenia), providing valuable markers in the prodromal phase of the diseases for early diagnosis and treatment.},
}

@article {pmid41822688,
year = {2026},
author = {Cortes-Flores, H and Torrandell-Haro, G and Brinton, RD},
title = {Immunotherapies for risk reduction in age-associated neurodegenerative diseases: impact of sex and treatment duration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.26347446},
pmid = {41822688},
abstract = {INTRODUCTION: Neurodegenerative diseases (NDDs) including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and non-AD dementias share chronic neuroinflammatory mechanisms that contribute to neuronal injury and disease progression. While anti-inflammatory therapies (AITs) are associated with reduced neurodegenerative disease risk, knowledge regarding the impact of biological sex and treatment duration across multiple NDDs remains limited.

METHODS: We conducted a retrospective cohort analysis using a large propensity-score-matched population (n = 190,308; 95,154 treated vs 95,154 untreated) to evaluate associations between long-term AIT exposure and incidence of major NDDs. Disease-specific and combined outcomes were assessed across drug classes (NSAIDs, corticosteroids, immunomodulators), sex, age, and therapy duration.

RESULTS: AIT exposure was associated with a significantly lower risk of developing any NDD (RR = 0.47, 95% CI 0.43-0.48, p < .0001) and was equally effective in both sexes. Risk reduction was observed for each individual disease: AD (RR = 0.40), non-AD dementia (RR = 0.51), PD (RR = 0.43), MS (RR = 0.25), and ALS (RR = 0.48). Among drug classes, immunomodulators conferred the largest reduction (RR = 0.19), followed by corticosteroids (RR = 0.41) and NSAIDs (RR = 0.42). Duration analyses revealed a graded benefit, with RR declining from 0.94 (<1 year) to 0.25 (>6 years). Risk reduction was strongest in older participants (75-79 years).

DISCUSSION: Chronic use of anti-inflammatory or immunomodulatory therapies was associated with substantially reduced incidence of multiple neurodegenerative diseases in both sexes. The strongest effects were observed with immunomodulator use and prolonged therapy duration, suggesting that sustained modulation of systemic inflammation confers broad neuroprotective effects in both sexes. These findings highlight the potential of targeting immune-inflammatory pathways for neurodegenerative disease prevention and can inform prospective mechanistic and interventional studies.},
}

@article {pmid41822355,
year = {2026},
author = {Fu, G and Tang, S and Sun, X and Tong, J and Zhou, M and Li, P and Meng, P and Cheng, S and Song, Z},
title = {Danggui Shaoyao San ameliorates neuroinflammation in a D-galactose-induced Alzheimer's disease rat model by suppressing the JAK2/STAT3 pathway and modulating Th17/Treg -related immune dysregulation.},
journal = {Frontiers in cell and developmental biology},
volume = {14},
number = {},
pages = {1763180},
pmid = {41822355},
issn = {2296-634X},
abstract = {OBJECTIVE: This study investigates the therapeutic potential of Danggui Shaoyao San (DSS), a traditional Chinese herbal formula, focusing on its effects on Th17/Treg -associated immune regulation and the JAK2/STAT3 signaling pathway.

METHODS: Forty male Sprague-Dawley rats were randomly divided into five groups: control, AD model, low-dose DSS (12 g/kg/day, raw herbal materials), high-dose DSS (24 g/kg/day, raw herbal materials), and donepezil (0.5 mg/kg/day). AD models were established by intraperitoneal injection of D-galactose (100 mg/kg/day) for 8 consecutive weeks. Behavioral tests, flow cytometry, biochemical assays, histological analyses, qPCR, and Western blotting were used to evaluate DSS's effects. Untargeted metabolomics profiled metabolic alterations, while network pharmacology and molecular docking were integrated to predict key targets and pathways.

RESULTS: DSS treatment significantly alleviated neuronal damage, suppressed neuroinflammation, and improved learning and memory deficits in AD rats. Moreover, DSS was associated with alterations in Th17- and Treg-related immune dysregulation both in the brain and periphery. Serum metabolomic identified disruptions lipid metabolism and amino acid metabolism pathways. Network pharmacology and experimental validation indicated that DSS exerts its anti-neuroinflammatory effects by inhibiting JAK2 and STAT3 phosphorylation, reducing their nuclear translocation, and consequently suppressing Th17 differentiation and pro-inflammatory cytokine production.

CONCLUSION: DSS is a promising candidate for AD treatment, with neuroprotective and cognitive-enhancing properties mediated through immunomodulation and JAK2/STAT3 pathway inhibition.},
}

@article {pmid41821998,
year = {2026},
author = {Naguy, A and Pridmore, S and Singh, A and Solanki, A},
title = {Psychopharmacotherapy of Alzheimer's Disease-What Do We Have at Hand?.},
journal = {Psychopharmacology bulletin},
volume = {56},
number = {2},
pages = {170-175},
pmid = {41821998},
issn = {2472-2448},
mesh = {Humans ; *Alzheimer Disease/drug therapy/psychology ; },
abstract = {~ Alzheimer's disease (AD) is a devastating relentlessly progressive illness for which currently there is no definitive curative treatment. The mainstay of treatment remains symptomatic, though. Psychopharmacotherapy is only part of a multi-pronged package of care involving caregivers. Herein, authors would shed light on the main pharmacological options at hand.},
}

Humans
*Alzheimer Disease/drug therapy/psychology

@article {pmid41820320,
year = {2026},
author = {Sharma, S and Sharma, U and Sethiya, NK and Singh, L},
title = {Recent Alzheimer's Research Targets Amyloid-β with Novel Phytochemicals and Pharmacological Strategies for Therapy.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098373086251201095903},
pmid = {41820320},
issn = {1874-6128},
abstract = {Advances in molecular-level research proposed the Amyloid-β (Aβ) pathway as a pathophysiological centre of Alzheimer's Disease (AD) progression. The biochemical alterations within the Aβ cycle represent a core biological hallmark of AD and offer promising targets for the development of disease-modifying therapies. However, the precise molecular mechanisms of the Aβ pathway, as well as the spatial and temporal dynamics that drive synaptic dysfunction, neurodegeneration, and the clinical onset of AD, remain active and intensive current research areas. In this work, we provide a comprehensive review and update of the extensive body of research in the field. We analyze data that highlights the differential relationships between various species of Amyloid-β (Aβ) and several biological mechanisms relevant to Alzheimer's Disease (AD), including tau-mediated processes, neuroimmune responses, inflammatory changes, and neurochemical imbalances. This review explores the role of amyloid β, clinical symptoms and mortality, FDA-approved drugs, immunotherapy, and different phytoconstituents used for Aβ-targeting therapy. Phytochemicals show potential in Alzheimer's disease treatment through their antioxidant, anti-inflammatory, and anti-amyloid properties, but challenges with bioavailability and blood-brain barrier permeability remain significant obstacles to their clinical effectiveness.},
}

@article {pmid41819555,
year = {2026},
author = {Martins, WC and Mendes, LRC and Junqueira, MC and Pereira, CMS and Gilbbert, PC and Schommer, SO and Campos, SS and Rodrigues, RPC and Santos, VRP and Brito, TM and Dobrachinski, F and Lima, E and Rios-Santos, F and Vandresen-Filho, S},
title = {Baru (Dipteryx alata) nut oil attenuates amyloid-β-induced cognitive deficits by modulating neuroinflammation and BDNF signaling pathway.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/1028415X.2026.2641534},
pmid = {41819555},
issn = {1476-8305},
abstract = {Introduction: Current treatments for Alzheimer's disease (AD) are primarily supportive and have limited efficacy in slowing disease progression. Therefore, the search for new therapeutic agents is essential to improve cognitive deficits or potentially prevent the advancement of this neurodegenerative disorder. Baru oil (BO) contains several bioactive compounds that may possess neuroprotective effects. However, no studies have investigated the potential beneficial effects of BO in the context of AD.Aim and Methods: This study aimed to investigate the neuroprotective effects of BO in a rodent model of AD. Mice were pretreated orally with vehicle or BO 1 or 3 g/kg/day for 45 days. On the 30th day, mice were infused i.c.v with amyloid-beta (Aβ) or PBS. A positive control group was orally treated with memantine (20mg/kg/day) for 15 days after Aβ or PBS infusion. Following behavioral assessments, mice were euthanized and the brains were removed for biochemical assays.Results: Similar to memantine treatment, pretreatment with both doses of BO prevented Aβ-induced memory impairments in the Morris water maze and the object recognition task. Pretreatment with BO 3g/kg/day prevented Aβ-induced increase in lipid peroxidation in the hippocampus. BO pretreatment mitigated the Aβ-induced reductions in hippocampal expression levels of BDNF, TrkB, and p-CREB. BO prevented the Aβ-induced increase in COX-2 and NOS-2 expression in the hippocampus.Conclusion: BO reversed Aβ-induced cognitive deficits. These neuroprotective effects were associated with the mitigation of hippocampal oxidative stress and neuroinflammation, alongside the restoration of the BDNF/TrkB/p-CREB signaling pathway. Our findings highlight Baru oil as a promising multifactorial therapeutic agent for AD.},
}

@article {pmid41819428,
year = {2026},
author = {Kiyak-Kirmaci, H and Hazar-Yavuz, AN and Polat, EB and Dogan, MO and Tok, F and Cilingir-Kaya, OT and Elcioglu, HK},
title = {Empagliflozin and dapagliflozin, Sodium Glucose Cotransporter 2 Inhibitors, may improve cognitive dysfunctions: in silico and in vivo findings.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116158},
doi = {10.1016/j.bbr.2026.116158},
pmid = {41819428},
issn = {1872-7549},
abstract = {Type 2 Diabetes Mellitus (T2D) accelerates cognitive decline through a complex interaction of metabolic, oxidative, inflammatory, and vascular pathways and is widely recognized as a significant risk factor for Alzheimer's disease (AD). Sodium-glucose cotransporter (SGLT)2 inhibitors are widely used in the treatment of T2D, and accumulating evidence suggests that they may influence neurodegenerative processes beyond their glycemic effects. In this context, the present study investigated the potential contributions of empagliflozin (EMPA) and dapagliflozin (DAPA) to cognitive function by evaluating their in silico interactions with targets associated with oxidative stress, inflammation, and neuroprotection, including SGLT1, SGLT2, acetylcholinesterase (AChE), superoxide dismutase (SOD), receptor for advance glycation end-products (RAGE), and interleukin (IL)-1β. Furthermore, cognitive impairments in streptozotocin/nicotinamide-induced T2D were investigated in vivo by behavioral tests in rats. Biochemical alterations in brain tissues were evaluated using ELISA measurements, which encompassed the levels of SOD, RAGE, and IL-1β. Hematoxylin and eosin (H&E) staining was used to evaluate the structure of hippocampal and cortical tissue for histological assessment. Molecular docking analyses indicated that EMPA showed notably stronger interactions with AD-relevant targets such as SGLT1/2 and AChE than DAPA. Both EMPA and DAPA elevated SOD levels in brain tissue. Consistent with these biochemical improvements, behavioral assessments demonstrated enhanced learning and memory performance in treated rats relative to the T2D group. Nonetheless, histological analyses revealed that both drugs produced improvements in the cortex and hippocampus. In conclusion, EMPA and DAPA may modulate T2D-associated AD through multiple metabolic pathways, and further investigation is warranted to elucidate their contributions.},
}

@article {pmid41819312,
year = {2026},
author = {Cai, G and Zhang, J and Jiao, J and Yan, M},
title = {Eukaryotic elongation factor 2 kinase (eEF2K): Mechanisms and pharmacological significance in metabolic diseases.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151385},
doi = {10.1016/j.ijbiomac.2026.151385},
pmid = {41819312},
issn = {1879-0003},
abstract = {Eukaryotic elongation factor 2 kinase (eEF2K) is an atypical Ca[2+]/calmodulin-dependent serine/threonine kinase that inhibits the elongation phase of protein synthesis by phosphorylating its sole known substrate, eukaryotic elongation factor 2 (eEF2). As protein synthesis is one of the most energy-intensive cellular processes, eEF2K functions as an energy-conservation mechanism under nutrient or energy stress, thereby maintaining cellular homeostasis. It has emerged as a central hub linking energy metabolism, cellular stress responses, and disease progression. In metabolic diseases, aberrant eEF2K activity contributes to pathological processes. In type 2 diabetes (T2D) and its complications, eEF2K modulates insulin signaling, mitochondrial function, and stress responses, whereas in atherosclerosis, it affects endothelial function, inflammation, and autophagy, promoting disease progression. Consequently, eEF2K is considered a promising therapeutic target. Despite increasing interest, systematic studies on eEF2K in metabolic regulation remain limited, and its precise roles in metabolic reprogramming, immune-inflammatory modulation, and stress adaptation are not fully elucidated. Pharmacological strategies-including direct inhibitors, indirect modulators, targeted protein degraders (TPD), and paradoxical activators-are under exploration, offering novel avenues for treatment. This review summarizes the structure and regulatory network of eEF2K, highlights its roles in energy metabolism, oxidative stress, autophagy, and inflammation, and discusses its pathophysiological significance and therapeutic potential in T2D, atherosclerosis (AS), and Alzheimer's disease (AD), providing insights for future research and drug development. In addition, eEF2K is regarded as a "central hub linking metabolic inflammation, protein translation, and autophagy," highlighting its potential as a target for TPD therapies. This perspective provides broader disease coverage, deeper mechanistic insights, and new directions for drug development in metabolic and neurodegenerative disorders.},
}

@article {pmid41818943,
year = {2026},
author = {Gu, L and Liu, J and Shan, X and Li, S and Zheng, M and Wang, C and Tan, Y and Zhuo, X and Li, Q and Yang, W and Zhang, X},
title = {Flavonoids of Ziziphora clinopodioides improve Alzheimer's cognitive impairment and inhibit NLRP3 inflammasome activation via autophagy-lysosome pathway.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {154},
number = {},
pages = {158028},
doi = {10.1016/j.phymed.2026.158028},
pmid = {41818943},
issn = {1618-095X},
abstract = {BACKGROUND: Ziziphora clinopodioides Lam. (Z. clinopodioides), a distinctive medicinal plant endemic to Xinjiang, is predominantly centers on cardiovascular diseases. However, its possible therapeutic value in neurologic conditions have not been thoroughly examined, especially in Alzheimer's disease (AD).

PURPOSE: This study elucidates the intervention effect and mechanism of Z. clinopodioides on cognitive dysfunction in vivo and in vitro.

METHODS: UPLC-Q-Exactive-HR MS/MS technology was employed to analysis the chemical components of Z. clinopodioides and that enter into the serum and brain. the extract of Z. clinopodioides and linarin were administered orally to 3 × Tg-AD mice. Behavioral assessments were carried out and AD-pathology indicator were detected. Additionally, network pharmacology and non-target metabolomics were combined to analyze the potential mechanism.

RESULTS: Flavonoids from Z. clinopodioides (ZCF) were identified as the main components, with linarin being the most abundant. ZCF and linarin improved spatial memory, reduced Aβ deposition and Tau phosphorylation, and suppressed glial cell activation. Mechanistically, ZCF and linarin decreased NLRP3 protein levels and NF-κB phosphorylation, while enhancing LC3B, p62, and Cathepsin D expression, resulting in reduced IL-1β and IL-18 secretion in 3 × Tg mice, HT22 cells or BV2 cells-effects reversed by autophagy inhibition. ZCF promoted NLRP3 and p62 co-localization, leading to NLRP3 degradation via autophagy without affecting its mRNA levels.

CONCLUSION: ZCF restores the autophagy-lysosome pathway and suppresses NLRP3 inflammasome activation, significantly improving cognitive dysfunction in 3 × Tg-AD mice, and highlighting ZCF or linarin as promising candidates for AD treatment.},
}

@article {pmid41818828,
year = {2026},
author = {Gao, J},
title = {MTC-MSFFNet: a multi-task classification model based on multi-source feature fusion for Alzheimer's disease.},
journal = {Biomedical physics & engineering express},
volume = {},
number = {},
pages = {},
doi = {10.1088/2057-1976/ae510f},
pmid = {41818828},
issn = {2057-1976},
abstract = {Predicting the stages of Alzheimer's disease (AD) is crucial for delaying disease progression and enabling early intervention. A large amount of existing research focuses on the classification of cognitively normal (CN), mild cognitive impairment (MCI), and AD. However, the two subtypes of MCI-stable mild cognitive impairment (sMCI) and progressive mild cognitive impairment (pMCI)-should not be overlooked. Therefore, this study aims to accurately diagnose the disease stage of patients (CN, MCI, or AD) and further distinguish between sMCI and pMCI. In this work, a multi-task classification model based on multi-source feature fusion, termed MTC-MSFFNet, is proposed to accomplish two diagnostic tasks: (1) CN vs. MCI vs. AD, and (2) sMCI vs. pMCI.We select the hippocampus (HIP) and entorhinal cortex (ERC) as feature maps for the three-class task, and the hippocampus (HIP) and gray matter (GM) for the sMCI/pMCI task. The MTC-MSFFNet integrates a multi-source feature fusion module which combining brain structure maps with structural magnetic resonance imaging (sMRI) data, a task-specific weight learning module guided by brain structural information, and dedicated task heads for each classification objective. The proposed method is evaluated on a mixed dataset constructed from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Open Access Series of Imaging Studies (OASIS). Experimental results demonstrate that MTC-MSFFNet achieves an average accuracy of 98.09% for CN vs. MCI vs. AD classification and 95.16% for sMCI vs. pMCI classification. These results indicate that the proposed approach has significant potential to assist clinicians in developing targeted and personalized treatment plans.},
}

@article {pmid41818703,
year = {2026},
author = {Tang, J and Sun, Y and Lin, X and Zhao, X and Mao, C and Wan, M and Li, J and Guan, Y},
title = {Energy Compensation Strategy: The Frontier of Neurodegenerative Disease Treatment.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00964},
pmid = {41818703},
issn = {1948-7193},
abstract = {Neurodegenerative diseases are a major threat to global public health. Recent studies have revealed that mitochondrial DNA damage and the imbalance of protein homeostasis during aging constitute the core pathological basis of neurodegeneration. The resulting energy metabolism disorders are the common pathogenic hubs of multiple neurodegenerative diseases. In this review, we focus on representative neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease, and systematically discuss their pathology related to metabolic disorders. We introduce various energy compensation strategies: (1) rebuilding the energy supply by enhancing mitochondrial function; (2) implementing systemic metabolic remodeling; (3) supplementing alternative energy substrates; (4) utilizing direct energy delivery technology. This review also highlights the technical bottlenecks of existing energy compensation strategies, guiding future research on neurodegenerative diseases.},
}

@article {pmid41818192,
year = {2026},
author = {Akan, O and Chandreswaran, V and Soldan, HD and Bierbrauer, A and Axmacher, N and Wolf, OT and Merz, CJ},
title = {Cortisol treatment impairs path integration and alters grid-like representations in the male human entorhinal cortex.},
journal = {PLoS biology},
volume = {24},
number = {3},
pages = {e3003661},
doi = {10.1371/journal.pbio.3003661},
pmid = {41818192},
issn = {1545-7885},
mesh = {Humans ; *Entorhinal Cortex/drug effects/physiology ; Male ; *Hydrocortisone/pharmacology/administration & dosage ; Magnetic Resonance Imaging ; Adult ; Young Adult ; *Spatial Navigation/drug effects/physiology ; Brain Mapping ; Caudate Nucleus/drug effects/physiology ; },
abstract = {Acute stress triggers the release of cortisol, which broadly affects cognitive processes. Path integration, a specific navigational process, relies heavily on grid cells in the entorhinal cortex. The entorhinal cortex contains glucocorticoid receptors and is therefore likely to be influenced by cortisol, though little is known about this relationship. Given the role of the entorhinal cortex in neurological diseases such as Alzheimer's Disease, investigating the effects of cortisol on this brain region may offer insights into how stress affects these diseases. In this study, we examined the effects of cortisol on human path integration in 39 healthy men across two sessions. On each day, they received either 20 mg cortisol or a placebo and performed a virtual homing task during functional magnetic resonance imaging (fMRI). Cortisol markedly impaired path integration performance, independent of incoming distance or the presence of spatial cues, but did not affect navigational pattern as measured by proximity to the landmark. fMRI results showed that cortisol increased the activation of right caudate nucleus in the presence of landmarks. Using a representational similarity analysis, we observed grid-like representations in the right entorhinal cortex specifically on day one under placebo, but these were diminished by cortisol. Grid-like representations were associated with PI performance dependent on the availability of spatial cues and cortisol administration, suggesting that cortisol may interfere with the typical relationship of grid cells and PI. Overall, the study indicates that cortisol-induced disruption in grid cell function in the entorhinal cortex may underly stress effects on path integration.},
}

Humans
*Entorhinal Cortex/drug effects/physiology
Male
*Hydrocortisone/pharmacology/administration & dosage
Magnetic Resonance Imaging
Adult
Young Adult
*Spatial Navigation/drug effects/physiology
Brain Mapping
Caudate Nucleus/drug effects/physiology

@article {pmid41818176,
year = {2026},
author = {Thapa, M and Kumari, A and Chin, CY and Choby, JE and Akbari, E and Bogati, B and Jin, F and Furr, E and Chopyk, DM and Koduri, N and Pahnke, A and Burns, TL and Elrod, EJ and Burd, EM and Weiss, DS and Grakoui, A},
title = {Translocation of bacteria from the gut to the brain in mice.},
journal = {PLoS biology},
volume = {24},
number = {3},
pages = {e3003652},
doi = {10.1371/journal.pbio.3003652},
pmid = {41818176},
issn = {1545-7885},
mesh = {Animals ; *Gastrointestinal Microbiome/physiology/drug effects ; *Brain/microbiology/metabolism ; Mice ; *Bacterial Translocation/physiology ; Diet, High-Fat/adverse effects ; Mice, Inbred C57BL ; Male ; Enterobacter cloacae/physiology ; Vagus Nerve/microbiology ; Dysbiosis/microbiology ; },
abstract = {Recent advances suggest a correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that bacteria can translocate directly from the gut to the brain in small numbers when mice are fed an atherogenic, high-fat diet (Paigen diet) that causes alterations in gut microbiome composition and gut barrier permeability. The bacteria were not found in other systemic sites or the blood, but were detected in the vagus nerve. Right cervical vagotomy reduced bacterial burden in the brain, implicating the vagus nerve as a conduit for bacterial translocation from the gut to the brain. Antibiotic treatment perturbed the composition of the gut microbiome and correspondingly changed the bacteria that localized to the brain in the setting of Paigen diet feeding. To further establish the gut as the origin of bacterial translocation to the brain, we gavaged exogenous Enterobacter cloacae into Paigen diet-fed mice, subsequently detecting the E. cloacae in the gut and brain. In addition, we monocolonized germ-free mice with E. cloacae and only cultured the bacteria from the brains of mice fed Paigen diet, but not those fed standard diet. Localization of bacteria to the brain in Paigen diet-fed mice was reversible with return to normal diet. Bacteria were also detected in the brain of murine models of Alzheimer's, Parkinson's, and autism spectrum disorder fed standard diet. These data reveal a bacterial translocation axis from the gut to the brain, impacted by environmental (diet) and genetic factors, and warrant further investigation to determine if this phenomenon also occurs in humans and to elucidate whether it may play a role in diverse neurological conditions.},
}

Animals
*Gastrointestinal Microbiome/physiology/drug effects
*Brain/microbiology/metabolism
Mice
*Bacterial Translocation/physiology
Diet, High-Fat/adverse effects
Mice, Inbred C57BL
Male
Enterobacter cloacae/physiology
Vagus Nerve/microbiology
Dysbiosis/microbiology

@article {pmid41815391,
year = {2026},
author = {Kumar, N and Jangid, K and Kumar, V and Dwivedi, AR and Kumar, V and Devi, B and Arora, T and Parkash, J and Kumar, V},
title = {Synthesis and biological evaluation of N/O-propargylated diarylpyrimidines as dual inhibitors of acetylcholinesterase and monoamine oxidase.},
journal = {RSC advances},
volume = {16},
number = {15},
pages = {13369-13380},
pmid = {41815391},
issn = {2046-2069},
abstract = {Alzheimer's disease is a complex neurological disorder and is becoming a global health concern as the population ages. Considering the complex aetiology of the disease and ineptness of single-targeted drugs, the development of multi-targeted drugs emerges as the most effective strategy for the treatment of the disease. Cholinesterases and monoamine oxidases are amongst the most widely explored targets in Alzheimer's disease, and their dual inhibition offers a promising approach for achieving multipotent therapeutic effects. Herein, we designed and synthesized a series of N/O-propargylated diaryl pyrimidines and evaluated their inhibitory activity against acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymes. Most of the compounds were found to be active against AChE, MAO-A and MAO-B. Amongst the synthesised derivatives of the series, compounds, compounds NV-1 and NV-9 exhibited a balanced multipotent activity profile against both the targets i.e. acetylcholinesterase and monoamine oxidase. Compounds NV-1 and NV-9 displayed IC50 values of 1.30 µM and 0.88 µM against AChE, 0.232 µM and 9.31 µM against MAO-A and 0.949 µM and 9.23 µM against MAO-B, respectively. In the reversibility inhibition studies, both the compounds were found to be reversible in nature. In kinetic inhibition studies, both NV-1 and NV-9 showed non-competitive inhibition for AChE. Additionally, NV-1 and NV-9 were found to be moderately neuroprotective in nature and exhibit no cytotoxicity at lower compound concentrations. In the partition coefficient studies (octanol/water), the compound NV-9 was found to be lipophilic in nature. Molecular docking studies illustrate their stability within the active cavity of both enzymes. Simulation studies confirmed the thermodynamic stability of these compounds within the cavity for up to 100 ns. Thus, the N/O-propargylated diarylpyrimidines have the potential to be developed as multipotent drugs for the treatment of Alzheimer's disease.},
}

@article {pmid41814795,
year = {2026},
author = {Xi, H and Yang, WM and Xie, WT and Yang, Y and Wei, WX and Li, H and Zhai, S},
title = {[Construction and evaluation of an animal model of Alzheimer's disease with spleen-kidney deficiency and stagnant phlegm syndrome based on formula test].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {3},
pages = {708-721},
doi = {10.19540/j.cnki.cjcmm.20251110.901},
pmid = {41814795},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/genetics/metabolism/physiopathology/drug therapy ; *Disease Models, Animal ; Male ; Mice ; Mice, Transgenic ; Mice, Inbred C57BL ; Humans ; *Spleen/physiopathology/drug effects ; *Kidney/physiopathology/drug effects ; Brain-Derived Neurotrophic Factor/metabolism/genetics ; },
abstract = {This study aims to establish a standardized mouse model of Alzheimer's disease(AD) with spleen-kidney deficiency and stagnant phlegm syndrome(AD-SKDSP) based on TCM theory, so as to provide a disease-syndrome combined model that aligns with the TCM diagnosis and treatment paradigm of "disease-syndrome-formula-efficacy" for modern research on AD prevention and treatment. Four-month-old male double-transgenic APP/PS1 mice were used as AD model animals. A standardized animal model of AD-SKDSP was constructed by high-sugar and high-fat diet feeding combined with ice-water bath and tail-clamping stimulation. The mice were randomly divided into an AD model group, an AD-SKDSP group, an AD Zhinao Capsule group, and a normal control group consisting of same-litter and age-matched male C57BL/6J mice. Corresponding drug treatments were administered at designated time points. During the eight-week modeling period, the following parameters were measured: physical sign scores, grip strength, body weight, 24-hour food intake, 24-hour fecal water content, female mouse fertility, Morris water maze performance, nose-tongue-collateral-foot color, hippocampus detected by hematoxylin-eosin(HE) staining, Aβ_(1-42) and brain-derived neurotrophic factor(BDNF) detected by immunohistochemistry, whole blood and plasma viscosity, 2-hour D-xylose, testosterone(T), estradiol(E_2), calcium(Ca), phosphorus(P), bone Gla protein(BGP), hippocampal synapsin(SYN) and postsynaptic density protein 95(PSD-95) mRNAs, and SYN, PSD-95, and BDNF proteins. The results showed that by the end of the 4th week, compared with the normal control group, the AD model group, AD-SKDSP group, and AD Zhinao Capsule group exhibited progressively increased physical sign scores and 24-hour fecal water content, and progressively decreased grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). Compared with the AD model group, the AD-SKDSP group and AD Zhinao Capsule group showed significantly increased physical sign scores and 24-hour fecal water content, along with significantly reduced grip strength, body weight, and 24-hour food intake(P<0.05, P<0.01). From the 5th week onward, compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant reductions in physical sign scores and 24-hour fecal water content, as well as significant increases in grip strength, body weight, and 24-hour food intake with prolonged intragastric administration of Zhinao Capsule(P<0.05, P<0.01). By the end of the 8th week, compared with the normal control group, the AD model group and AD-SKDSP group exhibited significantly decreased female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E_2, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression. Meanwhile, platform latency, hippocampal Aβ_(1-42) expression, and whole blood and plasma viscosity(low, medium, and high shear rates) were significantly increased, while platform crossings and target quadrant swimming time were markedly reduced(P<0.05, P<0.01). Hippocampal CA1 neurons in these groups displayed partial loss of normal morphology, with pyknotic or swollen nuclei, deep blue staining, disorganized distribution, and a thickness of "3-5" layers. Compared with the AD model group, the AD-SKDSP group showed significant reductions in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E_2, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant increases in platform latency, hippocampal Aβ_(1-42) expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant decreases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neurons exhibited irregular shapes, increased nuclear pyknosis, intensified deep blue staining, a thickness of "1-3" layers, and chaotic distribution. Compared with the AD-SKDSP group, the AD Zhinao Capsule group demonstrated significant increases in female fertility, corrected R/G/B values of nose-tongue-collateral-foot, hippocampal BDNF expression, levels of 2-hour D-xylose, T, E_2, Ca, P, and BGP, hippocampal SYN and PSD-95 mRNA expression, and SYN, PSD95, and BDNF protein expression, significant decreases in platform latency, hippocampal Aβ_(1-42) expression, and whole blood and plasma viscosity(low, medium, and high shear rates), and significant increases in platform crossings and target quadrant swimming time(P<0.05, P<0.01). The hippocampal CA1 neuronal pathology was markedly alleviated. In summary, guided by the holistic concept and syndrome differentiation theory of TCM and on the basis of characteristics of "spleen deficiency", "kidney deficiency", and "intermingled phlegm and blood stasis", this study successfully established a standardized AD-SKDSP animal model by combining a high-sugar and high-fat diet with ice-water bath and tail-clamping stimulation for eight weeks. This modeling method exhibits strong controllability, minimal physicochemical stimulation, reproducibility, and verifiability, providing a stable and standardized disease-syndrome combined animal model for future research on the "disease-syndrome-formula-efficacy" paradigm in AD-SKDSP.},
}

Animals
*Alzheimer Disease/genetics/metabolism/physiopathology/drug therapy
*Disease Models, Animal
Male
Mice
Mice, Transgenic
Mice, Inbred C57BL
Humans
*Spleen/physiopathology/drug effects
*Kidney/physiopathology/drug effects
Brain-Derived Neurotrophic Factor/metabolism/genetics

@article {pmid41814765,
year = {2026},
author = {Wu, D and Lai, BX and Wang, ZY and Niu, QX and Cai, YQ and Long, QH},
title = {[Protective effects of Suanzaoren Decoction on hippocampal neuron and its influence on PI3K/Akt signaling pathway in APP/PS1 transgenic mice].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {1},
pages = {173-180},
doi = {10.19540/j.cnki.cjcmm.20250930.701},
pmid = {41814765},
issn = {1001-5302},
mesh = {Animals ; *Hippocampus/drug effects/metabolism/cytology ; Male ; *Signal Transduction/drug effects ; Mice ; *Alzheimer Disease/drug therapy/genetics/metabolism ; *Drugs, Chinese Herbal/administration & dosage/pharmacology ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; *Neurons/drug effects/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; Mice, Transgenic ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/genetics/metabolism ; Apoptosis/drug effects ; Humans ; *Neuroprotective Agents/administration & dosage ; Presenilin-1/genetics/metabolism ; },
abstract = {This study explored the mechanism by which Suanzaoren Decoction(SZRD) ameliorates hippocampal neuronal damage in APP/PS1 mice by inhibiting Bax/Bcl-2/caspase-3-mediated apoptosis through the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway. Differentially expressed genes(DEGs) in Alzheimer's disease(AD) were screened using the GEO database, and KEGG and GO enrichment analyses were performed using R software. Thirty 6-month-old APP/PS1 transgenic mice were randomly assigned to three groups: APP/PS1 group, low-dose SZRD group(12.96 g·kg~(-1)), and high-dose SZRD group(25.92 g·kg~(-1)), while ten age-matched male C57BL/6J mice served as the blank control group. The treatment groups received SZRD by gavage for 28 consecutive days. Following treatment, spatial learning and memory were assessed using the Morris water maze test. Neuronal numbers were evaluated by Nissl staining. Immunohistochemistry(IHC) was used to detect neuron-specific nuclear protein(NeuN) and assess amyloid-β(Aβ) deposition in hippocampal neurons. Western blot was performed to measure the expression levels of PI3K/Akt pathway proteins and apoptosis-related markers, including Bcl-2, Bax, caspase-3, and cleaved-caspase-3 in hippocampal tissues. Bioinformatics analysis identified 686 DEGs, with GO enrichment linked to synaptic function and neurotransmitter transport, and KEGG pathways including neuroactive ligand-receptor interaction and PI3K/Akt signaling. In vivo experiments showed that, compared with APP/PS1 mice, both low-and high-dose SZRD groups exhibited improved learning and memory, increased neuronal numbers, and decreased Aβ deposition. Furthermore, hippocampal levels of p-PI3K/PI3K, p-Akt/Akt, and Bcl-2 were upregulated, while Bax and cleaved-caspase-3/caspase-3 levels were downregulated. In conclusion, SZRD may improve hippocampal neuronal damage and cognitive function in APP/PS1 mice by regulating Bax/Bcl-2/caspase-3-mediated apoptosis through the PI3K/Akt signaling pathway.},
}

Animals
*Hippocampus/drug effects/metabolism/cytology
Male
*Signal Transduction/drug effects
Mice
*Alzheimer Disease/drug therapy/genetics/metabolism
*Drugs, Chinese Herbal/administration & dosage/pharmacology
*Phosphatidylinositol 3-Kinases/metabolism/genetics
*Neurons/drug effects/metabolism
*Proto-Oncogene Proteins c-akt/metabolism/genetics
Mice, Transgenic
Mice, Inbred C57BL
Amyloid beta-Protein Precursor/genetics/metabolism
Apoptosis/drug effects
Humans
*Neuroprotective Agents/administration & dosage
Presenilin-1/genetics/metabolism

@article {pmid41814705,
year = {2025},
author = {Lai, BX and Wu, D and Niu, QX and Long, QH and He, LL},
title = {[Qiangji Decoction regulates AMPKα/Drp1/Nrf2 pathway to ameliorate neural damage induced by D-galactose by suppressing oxidative stress and neuronal apoptosis].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {50},
number = {24},
pages = {6967-6977},
doi = {10.19540/j.cnki.cjcmm.20250926.801},
pmid = {41814705},
issn = {1001-5302},
mesh = {Animals ; *Apoptosis/drug effects ; *Drugs, Chinese Herbal/administration & dosage/pharmacology ; *NF-E2-Related Factor 2/metabolism/genetics ; *AMP-Activated Protein Kinases/metabolism/genetics ; Mice ; *Oxidative Stress/drug effects ; *Neurons/drug effects/metabolism/cytology ; *Galactose/adverse effects ; Male ; Mice, Inbred C57BL ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; Signal Transduction/drug effects ; Humans ; Hippocampus/drug effects/metabolism ; },
abstract = {This study aims to investigate the mechanism by which Qiangji Decoction(QJD) regulates the adenosine 5'-monophosphate(AMP)-activated protein kinase α(AMPKα)/dynamin-related protein 1(Drp1)/nuclear factor E2 related factor 2(Nrf2) pathway to ameliorate oxidative stress and neuronal apoptosis induced by D-galactose. Seventy-two C57BL/6 mice were randomized into the control, model, low-dose Qiangji Decoction(L-QJD), medium-dose Qiangji Decoction(M-QJD), high-dose Qiangji Decoction(H-QJD), and metformin(Met) groups. The mouse model of Alzheimer's disease(AD) was established by subcutaneous injection of D-galactose(0.1 g·kg~(-1)) into the mouse neck for 8 consecutive weeks. The control and model groups received equal volumes of normal saline by gavage at a dose of 20 mL·kg~(-1), and the L-QJD, M-QJD, and H-QJD groups were treated with QJD extract at doses of 12.48, 24.96, and 49.92 g·kg~(-1), respectively. The Met group was administrated with metformin sustained-release tablets by gavage at a dose of 0.2 g·kg~(-1). After 4 weeks of treatment, the Morris water maze test was carried out to evaluate the learning and memory abilities of mice. The pathological changes of the hippocampus were observed via hematoxylin-eosin staining. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling staining was employed to detect apoptotic neurons in the hippocampus. Immunofluorescence(IF) staining was employed to detect the expression levels of B cell lymphoma-2(Bcl-2) and Bcl2-associated X protein(Bax) in the hippocampus. Biochemical assay kits were used to measure the levels of malondialdehyde(MDA), total superoxide dismutase(T-SOD), glutathione peroxidase(GSH-PX), and catalase(CAT) in the hippocampal tissue. Western blot was used to determine the expression levels of AMPKα, phosphorylated AMPKα(p-AMPKα-Thr172), Drp1, phosphorylated Drp1(p-Drp1-Ser616), cysteinyl aspartate-specific proteinase-3(caspase-3), cleaved caspase-3, Nrf2, heme oxygenase 1(HO-1), and NAD(P)H quinone oxidoreductase 1(NQO1) in the hippocampal tissue. The results showed that compared with the control group, the model group presented reduced learning and memory abilities, increased neurons with shrinkage or deep staining, increased apoptotic neurons(P<0.01), upregulated expression of Bax, MDA, p-Drp1-Ser616/Drp1, and cleaved caspase-3/caspase-3(P<0.01), and downregulated expression of Bcl-2, T-SOD, GSH-PX, CAT, p-AMPKα-Thr172/AMPKα, Nrf2, HO-1, and NQO1(P<0.01) in the hippocampus. Compared with the model group, the M-QJD, H-QJD, and Met groups showed improved learning and memory abilities, decreased neurons with shrinkage or deep staining and apoptotic neurons(P<0.05, P<0.01), downregulated expression of Bax, MDA, p-Drp1-Ser616/Drp1, and cleaved caspase-3/caspase-3 in the hippocampus(P<0.05, P<0.01), and upregulated expression of Bcl-2, T-SOD, GSH-PX, CAT, p-AMPKα-Thr172/AMPKα, Nrf2, HO-1, and NQO1 in the hippocampus(P<0.05, P<0.01). QJD could alleviate D-galactose-induced cognitive impairment, neuronal apoptosis, and oxidative stress by regulating the AMPKα/Drp1/Nrf2 pathway.},
}

Animals
*Apoptosis/drug effects
*Drugs, Chinese Herbal/administration & dosage/pharmacology
*NF-E2-Related Factor 2/metabolism/genetics
*AMP-Activated Protein Kinases/metabolism/genetics
Mice
*Oxidative Stress/drug effects
*Neurons/drug effects/metabolism/cytology
*Galactose/adverse effects
Male
Mice, Inbred C57BL
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
Signal Transduction/drug effects
Humans
Hippocampus/drug effects/metabolism

@article {pmid41814022,
year = {2026},
author = {Blujdea, ER and van Bokhoven, P and Martino-Adami, PV and Marshe, VS and Vromen, EM and Hok-A-Hin, YS and Boiten, WA and Irwin, DJ and Chen-Plotkin, AS and Lemstra, AW and Pijnenburg, Y and van der Flier, WM and Peters, O and Hellmann-Regen, J and Priller, J and Schneider, A and Wiltfang, J and Jessen, F and Düzel, E and Buerger, K and Perneczky, R and Teipel, S and Laske, C and Brosseron, F and , and Del Campo, M and Wijdeven, R and Visser, PJ and Tijms, BM and De Jager, PL and Ramirez, A and Teunissen, CE and Vermunt, L},
title = {Microglia protein profiles in CSF across Alzheimer's disease clinical stages.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
pmid = {41814022},
issn = {2662-8465},
support = {WE.03-2018-05//Alzheimer Nederland (Alzheimer Netherlands)/ ; WE.03-2018-05//Alzheimer Nederland (Alzheimer Netherlands)/ ; },
abstract = {Microglia are implicated in the progression of Alzheimer's disease (AD) pathology from its earliest stages, suggesting that cerebrospinal fluid (CSF) microglia profiling across clinical AD stages can aid in treatment development and monitoring. We analyzed two CSF cohorts (n = 834) that span from unimpaired controls to preclinical and dementia AD stages, identifying 109 dysregulated microglia-related proteins. Enrichment analyses revealed innate immune processes and cellular recruitment in preclinical AD, whereas AD dementia revealed adaptive immunity and macrophage responses. Next, we aligned the in vivo microglia protein profiles with ex vivo-derived microglial transcriptomic signatures, such as disease-associated microglia phenotypes. Transcriptomic signatures were not specific to either clinical stage but spanned both. We classified an 18-protein panel highlighting distinct changes between the preclinical and dementia stages. Our findings underscore the potential of microglia-based biomarker research for AD staging, offering insights into microglia dynamics in clinical AD stages and how transcriptomic signatures translate to proteomic profiles.},
}

@article {pmid41813040,
year = {2026},
author = {Araujo, AQC},
title = {The corporate takeover of Alzheimer's treatment: a crisis in neurological autonomy?.},
journal = {Arquivos de neuro-psiquiatria},
volume = {84},
number = {3},
pages = {1-5},
doi = {10.1055/s-0046-1817020},
pmid = {41813040},
issn = {1678-4227},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Neurology/ethics ; Brazil ; *Drug Industry/ethics ; Physician-Patient Relations/ethics ; Neurologists/ethics ; *Professional Autonomy ; *Antibodies, Monoclonal/therapeutic use ; United Kingdom ; United States ; },
abstract = {The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease represents a significant advancement in neurology. This accomplishment coincides with a worrisome trend: the increasing hegemony of large corporate healthcare organizations and commercial laboratory corporations in the supply of these new medications. This editorial examines how corporate influence undermines the traditional physician-patient relationship, diminishes neurologist autonomy, and signals a broader incursion into neurological practice by nonspecialists. The current situation in Brazil, compared with the United States and Europe, including the United Kingdom, is discussed, and strategies are proposed to maintain the integrity of neurological therapy amid growing corporate influence in the medical field.},
}

*Alzheimer Disease/drug therapy
Humans
*Neurology/ethics
Brazil
*Drug Industry/ethics
Physician-Patient Relations/ethics
Neurologists/ethics
*Professional Autonomy
*Antibodies, Monoclonal/therapeutic use
United Kingdom
United States

@article {pmid41812658,
year = {2026},
author = {Turnbull, A and Gross, JJ and Vankee-Lin, F},
title = {The emergence of neuropsychiatric symptoms in preclinical Alzheimer's disease: An emotion regulation perspective.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2026.01.022},
pmid = {41812658},
issn = {1097-4199},
abstract = {Preclinical Alzheimer's disease (AD) is associated with distressing neuropsychiatric symptoms (NPSs) that may accelerate progression toward dementia. Existing approaches probe the symptom-level domain-general or domain-specific neural correlates of NPSs. However, the field lacks process-oriented models of symptom emergence for targeted treatment. We propose one pathway for symptom emergence involving the disruption of emotion regulation (ER) systems by early AD pathology. AD pathology in the ventral anterior cingulate cortex-ventromedial prefrontal cortex disrupts model-free ER that modulates negative valuations using experience-dependent reinforcement learning (e.g., fear extinction), leading to increased negative valuations and negative affect. We further propose that model-based ER competes for overtaxed executive resources and is less successful in preclinical AD, particularly in demanding real-world contexts. These changes lead to a shift toward negative affect, leading to divergent trajectories of NPSs depending on critical moderators. We discuss implications for intervention to improve NPSs and potentially slow dementia progression.},
}

@article {pmid41811933,
year = {2026},
author = {El-Sabbagh, NA and Ellakwa, DE},
title = {AMP-activated protein kinase as a therapeutic target: effects of nano-selenium and thymoquinone in Alzheimer's disease.},
journal = {Archives of physiology and biochemistry},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13813455.2026.2640885},
pmid = {41811933},
issn = {1744-4160},
abstract = {CONTEXT: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and complex multifactorial pathogenesis. AMP-activated protein kinase (AMPK) has been identified as a promising molecular target in AD due to its neuroprotective functions, particularly in energy regulation.

OBJECTIVE: To evaluate the effects of nano-selenium and thymoquinone (TQ) on AMPK gene expression in an AD rat model.

SUBJECTS AND METHODS: Fifty male albino rats were divided into five groups. Four groups were induced with AD via lipopolysaccharide (LPS) injection, while the control group remained untreated. The experimental groups received nano-selenium, TQ, or a combination of both treatments. AMPK gene expression in brain tissue was measured using real-time PCR analysis.

RESULTS: Treatment with nano-selenium, TQ, or their combination significantly upregulated AMPK expression in brain tissue compared to untreated AD rats (p<0.001). The combination therapy produced the highest increase in AMPK expression.

DISCUSSION AND CONCLUSION: Nano-selenium and TQ enhance AMPK gene expression in AD, suggesting a potential therapeutic mechanism involving AMPK-related pathways.},
}

@article {pmid41810694,
year = {2026},
author = {Yu, L and Yokomizo, S and Doan, TH and Zhao, Q and Ganne, A and Balasubramaniam, M and Kastanenka, KV},
title = {Zolpidem restores sleep and decreases amyloid in a mouse model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71175},
doi = {10.1002/alz.71175},
pmid = {41810694},
issn = {1552-5279},
support = {R01AG066171/NH/NIH HHS/United States ; //Cure Alzheimer's Fund/ ; //Chan Zuckerberg Initiative DAF Fund/ ; //BrightFocus Foundation/ ; 202360054//Japan Society for the Promotion of Science/ ; PYJH2024314//Affiliated Hospital of Xuzhou Medical University/ ; },
mesh = {Animals ; *Zolpidem/pharmacology ; Mice ; Disease Models, Animal ; Mice, Transgenic ; *Alzheimer Disease/drug therapy ; *Sleep/drug effects ; *Plaque, Amyloid/pathology/drug therapy ; Electroencephalography ; Amyloid beta-Protein Precursor/genetics ; Brain/drug effects/metabolism ; Presenilin-1/genetics ; Male ; },
abstract = {INTRODUCTION: Deficits in non-rapid eye movement (NREM) sleep facilitate Alzheimer's disease (AD) progression. Enhancing gamma-aminobutyric acid-ergic (GABAergic) signaling can restore sleep. Unbiased computational analysis identified zolpidem as high-affinity GABA receptor modulator facilitating chloride transport that could slow AD.

METHODS: Zolpidem's effects on sleep and Alzheimer's progression were evaluated in young APP/PS1 (amyloid precursor protein/presenilin 1) mice. Sleep was monitored with electroencephalography/electromyography (EEG/EMG) telemetry. Wide-field imaging with voltage-sensitive dyes (VSDs) was used to track sleep-dependent brain rhythms. Multiphoton microscopy allowed assessments of amyloid plaque load and basal neuronal calcium levels. Behavioral assays were used to measure memory and cognitive function.

RESULTS: Zolpidem restored NREM sleep and rescued sleep-dependent brain rhythm, slow oscillation. Zolpidem administration reduced cortical amyloid plaque burden, mitigated neuronal calcium overload, and enhanced sleep-dependent contextual recall without adverse effects on locomotion.

DISCUSSION: Zolpidem effectively decreased amyloid in young APP/PS1 mice. This supports zolpidem's therapeutic promise as an intervention strategy at early stages of AD.

HIGHLIGHTS: Zolpidem treatment improves non-rapid eye movement (NREM) sleep stability and reduces sleep fragmentation. Zolpidem restores slow oscillation in young APP/PS1 (amyloid precursor protein/presenilin 1) mice. Zolpidem treatment reduces amyloid plaque burden and calcium overload in neurons. Zolpidem-treated mice show improved sleep-dependent memory consolidation. Sleep rhythm enhancement shows promise for Alzheimer's therapy.},
}

Animals
*Zolpidem/pharmacology
Mice
Disease Models, Animal
Mice, Transgenic
*Alzheimer Disease/drug therapy
*Sleep/drug effects
*Plaque, Amyloid/pathology/drug therapy
Electroencephalography
Amyloid beta-Protein Precursor/genetics
Brain/drug effects/metabolism
Presenilin-1/genetics
Male

@article {pmid41809690,
year = {2025},
author = {Noshin, K and Hou, B and Boland, MR and Wen, Z and Tong, B and Shen, L and Zhang, A},
title = {IRIS: Interpretable Risk Clustering Intelligence for Survival Analysis.},
journal = {Proceedings : ... IEEE International Conference on Big Data. IEEE International Conference on Big Data},
volume = {2025},
number = {},
pages = {1143-1152},
pmid = {41809690},
issn = {2639-1589},
abstract = {Survival analysis models have evolved significantly with deep learning approaches, yet often lack interpretability and meaningful risk stratification capabilities. We present Interpretable Risk Clustering Intelligence for Survival Analysis (IRIS), a novel framework that addresses the critical task of risk clustering while enhancing both input-level and model-body interpretability. Unlike traditional survival models that perform post-hoc risk clustering, IRIS learns to cluster patients into meaningful risk groups directly from data while providing transparent feature importance estimation through feature contribution functions. We validate IRIS on several benchmark datasets, a real-world Alzheimer's disease dataset, and an electronic health record dataset, showing superior performance in risk clustering and predictive reliability with only a modest decrease in time-to-event prediction accuracy compared to state-of-the-art methods. Our results show that IRIS successfully balances the trade-off between interpretability and prediction performance in risk-based survival analysis, offering clinicians actionable insights for treatment planning and resource allocation.},
}

@article {pmid41809632,
year = {2026},
author = {Mazurek, CY and Kaniuk, JK and Ahuja, CS},
title = {Mesenchymal stem cells and the central nervous system: historical perspectives and future directions.},
journal = {Frontiers in molecular neuroscience},
volume = {19},
number = {},
pages = {1742864},
pmid = {41809632},
issn = {1662-5099},
abstract = {Mesenchymal stem cells (MSCs) have been studied as a potential therapy for a wide range of conditions for approximately 30 years. MSCs have shown promise in treating pathologies of or affecting the central nervous system (CNS), specifically Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, spinal cord injury (SCI), traumatic brain injury (TBI), degenerative disc disease (DDD), and sepsis/meningitis. The therapeutic benefits of MSCs derive primarily from their arsenal of secreted factors that promote anti-inflammatory and pro-survival pathways while attenuating harmful immune responses, thus making them powerful immunomodulatory entities which are also capable of affecting a diverse range of cellular functions to promote endogenous mechanisms of repair. This review summarizes the current state of clinical trials research regarding pathologies of the CNS with a focus on historical progression and upcoming trials. We take a mechanistic approach to explain the therapeutic basis of MSCs and how this has informed clinical trials. We also mention the role of the MSC secretome and MSC exosomes in the treatment of CNS pathologies as well as their increasing use in clinical trials. Finally, we address the challenges inherent to the clinical translation and implementation of MSC therapies along with future directions of the field.},
}

@article {pmid41809245,
year = {2026},
author = {Bertrand, F and Strauss, M and Leurquin-Sterk, G and Lesage, V and Vandenberghe, M and Fery, P and Maenhout, C and Bier, JC},
title = {When images come to life: a case series.},
journal = {BMJ neurology open},
volume = {8},
number = {1},
pages = {e001352},
pmid = {41809245},
issn = {2632-6140},
abstract = {BACKGROUND: Delusional misidentification syndromes (DMS) involve erroneous identification of people, objects or places. They have been described in several psychiatric and neurological diseases, particularly in cognitive disorders and dementia. We report an unusual form of DMS in patients with dementia: the belief that individuals depicted in photographs or static images are alive.

METHODS: In this retrospective analysis, four patients followed in our memory clinic between March 2009 and June 2025 were selected for having developed, during follow-up, the belief that individuals depicted in two-dimensional representations were alive, as reported by themselves or caregivers. A standardised neuropsychological battery assessed the main cognitive domains. Final diagnoses were established during multidisciplinary consensus meetings based on neuropsychological assessments, brain MRI, 18F-FDG-PET, DaT-scan results (when available) and cerebrospinal fluid (CSF) biomarkers. Clinical data are detailed in this study.

RESULTS: All four patients exhibited core delusions in the context of dementia, with heterogeneous severity, symptom duration and treatment response, but all showed marked emotional-behavioural involvement and functional decline. Neuroimaging demonstrated widespread frontoparietotemporal hypometabolism with consistent right-hemispheric involvement; two patients had predominant left-sided hypometabolism without clinical differences. CSF biomarkers indicated Alzheimer's pathology in all cases, and probable dementia with Lewy bodies was diagnosed in two patients based on core clinical features, including a positive DaT-scan in one of them.

CONCLUSIONS: We describe a previously unreported DMS variant-'animated picture syndrome'-characterised by the belief that individuals depicted in photographs or static images are alive, sometimes leading to behaviours such as reluctance to leave home or preparing food for them. In our series, this syndrome emerged in the context of neurodegenerative disease and coincided with cognitive and functional decline. Its recognition may help identify clinical deterioration and prompt appropriate aetiological work-up, caregiver education and therapeutic interventions. Further studies should clarify its prevalence, mechanisms and relationship with other DMS variants.},
}

@article {pmid41809238,
year = {2026},
author = {Lam, TK and Rhind, SG and Tenn, C and Nakashima, A and Shiu, MY and King, K and Caddy, N and Vallikanthan, J and Crouzat, M and Lester, L and Vartanian, O},
title = {One is not like the other: Examining the neural response to repetitive low-level blast exposure in experienced military personnel.},
journal = {Neuroimage. Reports},
volume = {6},
number = {1},
pages = {100335},
pmid = {41809238},
issn = {2666-9560},
abstract = {BACKGROUND: Military members often report concussion-like symptoms from repetitive low-level blast (LLB) exposure, defined as overpressure from outgoing munitions like rifles and explosive breaching. Typically, the early stages of concussion and other neurological conditions (e.g., Alzheimer's Disease) lead to hyperconnectivity which is a transient and adaptive brain response to strengthen and establish neural connections to restore brain function. Over time, however, chronic hyperconnectivity can contribute to neurodegeneration. To determine whether LLB exposure also exhibits this connectivity trajectory, this study investigated the neural signature of LLB at two time points: At the chronic stage extrapolated from the duration of an individual's occupational career, and following a recent and concentrated blast regimen.

METHODS: Forty-six military breachers and snipers underwent a resting state functional magnetic resonance imaging brain scan before and after a training course. Graph theory was used to study the whole-brain network, cross-validated by a principal components analysis (PCA) conducted post-hoc. The pre-course scan was analyzed separately to examine the neural effects of chronic LLB exposure. The pre- and post-course scans were compared to examine the neural effects of recent blast exposure. Military controls without occupational breaching and/or sniping experience underwent the same protocol.

RESULTS: At pre-course, breachers and snipers exhibited hyperconnectivity compared to controls. However, after undergoing a recent LLB regimen, only breachers showed hypoconnectivity post-course relative to pre-course compared to controls.

CONCLUSION: The mechanism of repeated LLB overpressure and its associated neural response to this exposure appear to be specific to this condition. Characterizing LLB exposure can help refine assessment and treatment.},
}

@article {pmid41808725,
year = {2026},
author = {Narasimman, V and Devendran, D and Balasingam, P and Ravi, V and Vijayan, K},
title = {Neuroprotective potential of silver nanoparticles synthesized using Sargassum polycystum in a Zebrafish model of Alzheimer's disease.},
journal = {3 Biotech},
volume = {16},
number = {4},
pages = {121},
pmid = {41808725},
issn = {2190-572X},
abstract = {UNLABELLED: Silver nanoparticles were biosynthesized using an aqueous extract of the brown seaweed Sargassum polycystum and evaluated for their neuroprotective potential in an aluminium chloride (AlCl3)-induced zebrafish model of neurotoxicity. Physicochemical characterization confirmed stable, spherical nanoparticles with a surface plasmon resonance peak at 445 nm, nanoscale size distribution, and negative zeta potential, indicating good colloidal stability. The synthesized AgNPs exhibited moderate antioxidant activity in DPPH and ABTS assays. Embryo toxicity assessment demonstrated biocompatibility at lower concentrations, while higher doses produced concentration associated developmental toxicity. In adult zebrafish, AlCl3 exposure induced significant locomotor impairment, anxiety-like behaviour, and cognitive deficits. Co-treatment with AgNPs, particularly at 100 µg/L, significantly improved locomotor activity, reduced anxiety-associated behaviours, and restored learning and memory performance. Biochemical analyses showed a significant reduction in malondialdehyde levels and acetylcholinesterase activity in AgNP-treated groups, indicating Attenuation of oxidative stress and cholinergic dysfunction. Histopathological evaluation further confirmed preservation of neuronal architecture and reduced neurodegeneration following AgNP treatment. Based on the results indicate that S. polycystum derived silver nanoparticles provide concentration associated neuroprotection against aluminium chloride -induced neurotoxicity in zebrafish and May represent a promising green nanotherapeutic approach for neurodegenerative disorders.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04716-z.},
}

@article {pmid41807703,
year = {2026},
author = {Guo, S and Jin, H and Sun, H and Huang, S and Chen, Y and Chang, Y and Zhang, Y and Ding, L and Chen, S and Fu, C and Yin, Y and Cheng, W},
title = {TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41807703},
issn = {1757-4684},
support = {82472014//MOST | National Natural Science Foundation of China (NSFC)/ ; 24ZR1450000//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; 23ZR1441200//STCSM | Natural Science Foundation of Shanghai Municipality ()/ ; },
abstract = {Pathological TAR DNA-binding protein-43 (TDP-43) is a defining feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). However, the mechanism by which TDP-43 pathology disrupts microglial function and drives neuroinflammation remains unclear. In this study, we demonstrated that cytoplasmically mis-localized TDP-43 exacerbated neuroinflammation, induced cell death, and impaired phagocytic function in microglial cells, primarily through receptor interacting serine/threonine kinase 3 (RIPK3)-dependent necroptosis. Pharmacological inhibition of RIPK3 with GSK872 markedly attenuated these pathological effects in vitro. These findings were further corroborated in a murine model with cytoplasmic TDP-43 mis-localization, where GSK872 treatment remarkably alleviated neuroinflammation and restored cognitive deficits. Mechanistically, our findings indicate that the nuclear depletion of TDP-43, resulted from its cytoplasmic mis-localization, impairs its ability to transcriptionally repress the Ripk3 gene, subsequently leading to RIPK3 upregulation and activation of RIPK3-dependent necroptosis. Collectively, our findings establish RIPK3-dependent necroptosis as a critical driver of TDP-43 pathology-mediated neuroinflammation and identified necroptosis as a promising therapeutic target in TDP-43-associated neurodegenerative disorders.},
}

@article {pmid41803942,
year = {2026},
author = {Mueller, A and Jovalekic, A and Chapleau, M and Seidel, J and Ritter, M and Bickel, EM and Kiessling, N and MacSweeney, E and Stephens, AW and Koglin, N},
title = {In-vitro interaction studies between the amyloid PET tracer florbetaben and the amyloid-beta targeting antibodies lecanemab and donanemab on AD brain samples reveal no interferences.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41803942},
issn = {1758-9193},
abstract = {BACKGROUND: Amyloid PET imaging enables the in vivo visualization and quantification of amyloid-beta deposits in the brain. In research and clinical settings, it is further used to monitor amyloid-beta burden as well as the biological response to disease-modifying therapies. Amyloid-beta targeting monoclonal antibodies (mAbs) such as lecanemab and donanemab were designed to reduce brain amyloid-beta burden. If the PET tracer and the mAbs would bind to the same site, the PET signal may be impacted in patients undergoing therapy. Binding interaction studies were conducted to verify the reliability of PET readouts in this setting. The aim of this study was to investigate whether lecanemab or donanemab interfere with the binding of the amyloid PET tracer florbetaben to aggregated amyloid-beta deposits in vitro.

METHODS: Human Alzheimer’s disease (AD) brain tissue from various sources was used to assess potential interactions between florbetaben and lecanemab or donanemab. Three complementary approaches were used to confirm target binding and to study potential interactions: (1) competitive immunohistochemistry (IHC), (2) competitive autoradiography (ARG), and (3) ligand binding assays (LBA).

RESULTS: Across all three sets of experiments, no evidence of competition or inhibition of florbetaben binding to amyloid-beta deposits by lecanemab or donanemab was observed. Autoradiography demonstrated robust tracer binding to amyloid-beta plaques that was unaffected by incubation with excess antibody. Similarly, IHC and LBA experiments confirmed that florbetaben and the tested mAbs target distinct binding sites on amyloid-beta aggregates.

CONCLUSIONS: These results demonstrate that neither lecanemab nor donanemab interfere with florbetaben binding to amyloid-beta plaques in vitro, further validating its use in this setting. While the current data are limited to in-vitro experiments, they further support the use of florbetaben PET for monitoring amyloid-beta changes during treatment with amyloid-beta targeting therapies.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02001-y.},
}

@article {pmid41803833,
year = {2026},
author = {Feng, X and Liu, J and Liang, Z and Du, X and Zhao, L and Xie, N and Chen, C and Ding, L and Xia, X and Zheng, JC and Liu, J},
title = {Transcranial magnetic stimulation mitigates perioperative neurocognitive disorders by regulating the function of the glymphatic system.},
journal = {Cell communication and signaling : CCS},
volume = {24},
number = {1},
pages = {},
pmid = {41803833},
issn = {1478-811X},
support = {Nos. 82171194 and 82371204//the National Natural Science Foundation of China/ ; },
abstract = {UNLABELLED: The incidence of perioperative neurocognitive disorders (PND) increase with age, especially within those countries facing great challenge of aging population. However, the mechanism of PND remains elusive, and the lack of precautions has resulted in extended recovery among the elderly. Transcranial magnetic stimulation (TMS) has shown promising therapeutic potential in many neurological disorders such as depression and Alzheimer’s disease. This study aimed to explore the therapeutic potential of TMS on PND mouse model and aged patients. PND mice model were established through exploratory laparotomy on aged mice. We performed Y maze test and novel object recognition test to evaluate the cognitive function after TMS treatment. Intracisternal injection and immunofluorescence staining were conducted to assess the glymphatic system function. We used ELISA, immunofluorescence staining, Western-blotting and TUNEL assay to detect neuroinflammation and neuronal loss. We examined the therapeutic effect of TMS on patients in a clinical trial. PND mice showed improved cognitive functions after TMS treatment. TMS abrogated glymphatic system dysfunction and aquaporin-4 (AQP4) translocation, the key pathological changes that lead to cognitive decline, in PND mice. Moreover, TMS alleviated neuroinflammation and apoptosis in PND mice. We further found that inhibition of glymphatic system function blocked the ameliorative effects of TMS on postoperative cognitive function, neuroinflammation, and neuronal damage. Patients who received TMS showed improved memory function 7 days after surgery and obtained better Abbreviated Mental Test Score 30 days post-operation. Our study indicates the great therapeutic potentials of TMS in anesthesia- and surgery-induced cognitive impairment and pathological changes. Trial registration ChiCTR2200057080.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02751-0.},
}